WO2022261030A1 - Oligonucleotide analogue modulators of oncogenes - Google Patents

Oligonucleotide analogue modulators of oncogenes Download PDF

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Publication number
WO2022261030A1
WO2022261030A1 PCT/US2022/032403 US2022032403W WO2022261030A1 WO 2022261030 A1 WO2022261030 A1 WO 2022261030A1 US 2022032403 W US2022032403 W US 2022032403W WO 2022261030 A1 WO2022261030 A1 WO 2022261030A1
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unit
compound
wild type
guanidinobut
group
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PCT/US2022/032403
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French (fr)
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Dietrich A. Stephan
Ramesh U. BATWAL
Barry BADEAU
Austin KILGORE
Dani STOLTZFUS
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Neubase Therapeutics, Inc.
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Publication of WO2022261030A1 publication Critical patent/WO2022261030A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/595—Polyamides, e.g. nylon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C07K14/003—Peptide-nucleic acids (PNAs)

Definitions

  • Ras proteins are proto-oncogenes that are frequently mutated in human cancers. Ras proteins are encoded by three ubiquitously expressed genes: HRAS, KRAS, and NRAS. HRAS, KRAS, and NRAS are GTPases that function as molecular switches regulating pathways responsible for proliferation and cell survival. Aberrant Ras function is associated with hyperproliferative developmental disorders and cancer.
  • the present disclosure provides a compound comprising:
  • a pharmacophore wherein the pharmacophore is a region that comprises a structure that interferes with expression of a cancer-causing protein
  • oligomeric sequence comprises a repeating unit of formula: ionized form thereof, wherein:
  • R 1 is H, alkyl, or a nitrogen atom protecting group
  • R 2 is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3 is H, alkyl, or a nitrogen atom protecting group
  • R 4 is H, alkyl, or a nitrogen atom protecting group
  • R 5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the present disclosure provides a compound comprising a structure that is: wherein: the number of units with variables defined independently is at least 11;
  • N-Terminus is H, acyl, a group that together with the nitrogen atom to which the N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R 1 is a hydroxyalkyl group; each R alpha is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, O-alkyl, a peptide sequence, or NH 2
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent
  • LI is a linker group or absent
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof, wherein the compound interferes with expression of a cancer-causing protein.
  • FIG. 1 illustrates in vivo tumor growth inhibition via RNA targeting of G12D mutation using Compound 1.
  • Panel A illustrates the cell-signaling pathway downstream of RAS.
  • Panels B-E illustrate reduction in aberrant signaling across multiple pathway members downstream of RAS, such as MEK (Panel B), ERK (Panel C), CREB (Panel D), and RSK3 (Panel E), using Compound 1.
  • FIG. 3 illustrates in vivo tumor growth inhibition via RNA targeting of G12V mutation using Compound 2.
  • FIG. 4 shows the effect of Compound 5 and Compound 6 on HPAFII tumor volume when administered at a dose of 0.3 ⁇ M, 3 ⁇ M, 10 ⁇ M, or 30 ⁇ M (IT; QWx3).
  • FIG. 5 shows the effect of Compound 5 and Compound 6 on body weight of mice inoculated with HPAFII cells when administered at a dose of 0.3 ⁇ M, 3 ⁇ M, 10 ⁇ M, or 30 ⁇ M (IT; QWx3).
  • FIG. 6 shows the effect of treatment on tumor volumes when animals were treated with vehicle, 0.1 mg/kg of Compound 6, and 0.3 mg/kg of Compound 6.
  • FIG. 7 Panel A shows results of an IYT assay using DNA coding for either wild type K-Ras or G12Y mutated K-Ras and treated with Compound 7 or Compound 8.
  • Panel B shows the effect of treatment with Compound 7 or Compound 8 on tumor volumes in animals treated with 0 ⁇ M, 0.3 ⁇ M, 3 ⁇ M, 10 ⁇ M, or 30 ⁇ M of the compounds.
  • FIG. 8 shows the effect of treatment on tumor volumes when animals were treated with vehicle, 0.1 mg/kg of Compound 7, and 0.3 mg/kg of Compound 7.
  • FIG. 9 Panel A shows the effect of Compound 7 and Compound 9 on SHP-77 tumor volume when administered at a dose of 10 ⁇ M or 30 ⁇ M (IT).
  • Panel B shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compound 7 and Compound 9.
  • FIG. 10 shows the effect of Compound 7 and Compound 9 on the body weight of mice inoculated with SHP-77 cells when administered at a dose of 10 ⁇ M or 30 ⁇ M (IT).
  • FIG. 11 Panel A shows the results of the cell viability assay of HPAF-II cells treated with 1 ⁇ M or 5 ⁇ M Compound 6 compared to controls (control cells untreated, HPAF-II; cells treated only with the transfection reagent Lipofectamine 2000, HPAF-II Lipo).
  • Panel B shows cell cycle arrest results of HPAF-II cells treated with 1 ⁇ M or 5 ⁇ M Compound 6 compared to controls (control cells untreated, Mock; cells treated only with the transfection reagent Lipofectamine 2000, Lipo only).
  • FIG. 12 Panel A shows mRNA levels for KRAS alleles treated with Compound 6 as measured by qRT-PCR.
  • Panel B shows G12D mutant KRAS protein levels when cells were treated with Compound 6 as measured by western blot.
  • FIG. 13 Panel A shows the results of the cell viability assay of Capan2 cells treated with 1 ⁇ M or 5 ⁇ M Compound 7 compared to controls (control cell untreated, Capan2; cells treated only with the transfection reagent Lipofectamine 2000, Capan2 Lipo).
  • Panel B shows cell cycle arrest results of Capan2 cells treated with 1 pM or 5 pM Compound 7 compared to controls (control cell untreated, Mock; cells treated only with the transfection reagent Lipofectamine 2000, Lipo only).
  • FIG. 14 Panel A shows mRNA levels for KRAS alleles treated with Compound 7 as measured by qRT-PCR.
  • Panel B shows G12V mutant KRAS protein levels when cells were treated with Compound 7 as measured by western blot.
  • FIG. 15 Panel A shows results of an IVT assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compound 51.
  • Panel B shows the effect of treatment with Compound 51 on tumor volume in animals treated with control (PBS buffer); control (glucose buffer); 30 ⁇ M Compound 51 (PBS); 10 mg/kg Compound 51 (PBS); 30 ⁇ M Compound 51 (glucose buffer); or 10 mg/kg Compound 51 (glucose buffer).
  • FIG. 16 Panel A shows results of an SHP77 IVT assay using DNA coding for either wild type K-Ras or G12Y mutated K-Ras and treated with Compound 76 or Compound 90.
  • Panel B shows the effect of treatment with Compound 76 or Compound 90 on tumor volume in animals treated with control (PBS vehicle); Compound 76 at 60 pM/dose; Compound 76 at 120 pM/dose; or Compound 90 at 120 pM/dose.
  • FIG. 17 Panel A shows results of a Capan2 IVT assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compound 76 or Compound 90.
  • Panel B shows the effect of treatment with Compound 76 or Compound 90 on tumor volume in animals treated with glucose control; Compound 76 at 30 mg/kg; Compound 90 at 5 mg/kg; and Compound 90 at 30 mg/kg.
  • FIG. 18A Panels A-D show that mice treated with Compounds 5 and 6 with HPAF-II tumors sacrificed on days 25-30 post-first dose exhibited decreased KRAS downstream signaling between 11 and 16 days post-last dose.
  • Panel A shows G12D mutated K-Ras (RasG12D) relative to wild type K-Ras
  • Panel B shows G12V mutated K-Ras (RasG12V) relative to wild type K-Ras
  • Panel C shows P90RSK (via phospho-P90RSK T359/S363)
  • Panel D shows RSK3 (via phospho-RSK3 T356/S360).
  • FIG. 18B Panels E-H show that mice treated with Compounds 5 and 6 with HPAF-II tumors sacrificed on days 25-30 post-first dose exhibited decreased KRAS downstream signaling between 11 and 16 days post-last dose.
  • Panel E shows MEK (via phospho-MEKl/2 S217/S221)
  • Panel F shows ERK (via phospho-ERK T202/Y204)
  • Panel G shows MSK1 (via phospho-MSKl S360)
  • Panel H shows CREB (via phospho-CREB SI 33).
  • FIG. 19A Panels A-D show the level of decreased KRAS signaling observed in SHP77 tumors treated with Compound 7 and Compound 9.
  • Panel A shows G12D mutated K-Ras (RasG12D) relative to wild type K-Ras
  • Panel B shows G12V mutated K-Ras (RasG12V) relative to wild type K-Ras
  • Panel C shows P90RSK (via phospho-P90RSK T359/S363)
  • Panel D shows RSK3 (via phospho-RSK3 T356/S360).
  • FIG. 19B Panels E-H show the level of decreased KRAS signaling observed in SHP77 tumors treated with Compound 7 and Compound 9.
  • Panel E shows MEK (via phospho-MEKl/2 S217/S221)
  • Panel F shows ERK (via phospho-ERK T202/Y204)
  • Panel G shows MSK1 (via phospho-MSKl S360)
  • Panel H shows CREB (via phospho-CREB SI 33).
  • Panels A-F show that no cell signaling differences were observed in KRAS downstream signaling pathways at 43 days post-first injection in Capan-2 xenograft tumors treated with Compound 7 or Compound 8.
  • Panel A shows G12D mutated K-Ras (RasG12D)
  • Panel B shows G12V mutated K-Ras (RasG12V)
  • Panel C shows G12V mutated K-Ras (RasG12V) relative to wild type K-Ras
  • Panel D shows CREB (via phospho-CREB S133)
  • Panel E shows MSK1 (via phospho-MSKl S360)
  • Panel F shows P90RSK (via phospho- P90RSK T359/S363).
  • Panels A-E show that no cell signaling differences were observed in KRAS downstream signaling pathways at 43 days post-first injection in Capan-2 xenograft tumors treated with Compound 7 or Compound 8.
  • Panel A shows G12D mutated K-Ras (RasG12D) relative to wild type K-Ras
  • Panel B shows wild type K-Ras
  • Panel C shows MEK (via phospho-MEKl/2 S217/S221)
  • Panel D shows ERK (via phospho-ERK T202/Y204)
  • Panel E shows RSK3 (via phospho-RSK3 T356/S360).
  • FIG. 22 Panel A shows changes in mRNA levels of KRAS in A427 cells treated with control, Endo-Porter only, and Endo-Porter and Compound 6.
  • Panel B shows changes in mRNA levels of KRAS in HPAF-II cells treated with control, Endo-Porter only, and Endo-Porter and Compound 6.
  • Panel C shows changes in mRNA levels of KRAS in PANC1 cells treated with control, Endo-Porter only, and Endo-Porter and Compound 6.
  • FIG. 23 Panel A shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 5, 6, and 11-17.
  • Panel B shows the results of an IVT assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compounds 7-9 and 18-29.
  • Panel C shows the results of an IVT assay using DNA coding for either wild type K-Ras or G12C mutated K-Ras and treated with Compounds 30-42.
  • FIG. 24 shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 43-69.
  • FIG. 25 Panel A shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compounds 70-95.
  • Panel B shows the results of an IVT assay using DNA coding for either wild type K-Ras or G12C mutated K-Ras and treated with Compounds 96-110.
  • IVT in vitro transcription and translation
  • FIG. 26 Panel A shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 204-220 at 0.5 ⁇ M.
  • Panel B shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 204-220 at 0.25 ⁇ M.
  • FIG. 27 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e g. natural, modified, or non-natural nucleobases) or hydrogen.
  • R is a nucleobase (e g. natural, modified, or non-natural nucleobases) or hydrogen.
  • FIG. 28 illustrates the structure of Compound 5.
  • FIG. 29 illustrates the structure of Compound 8.
  • FIG. 30 illustrates the structure of Compound 9.
  • FIG. 31 illustrates the structure of Compound 11.
  • FIG. 32 illustrates the structure of Compound 12.
  • FIG. 33 illustrates the structure of Compound 26.
  • FIG. 34 illustrates the structure of Compound 62.
  • FIG. 35 illustrates the structure of Compound 63.
  • FIG. 36 illustrates the structure of Compound 69.
  • FIG. 37 illustrates the structure of Compound 71.
  • FIG. 38 illustrates the structure of Compound 75.
  • FIG. 39 illustrates the structure of Compound 76.
  • FIG. 40 illustrates the structure of Compound 90.
  • FIG. 41 illustrates the structure of Compound 93.
  • Ras proteins are proto-oncogenes that are frequently mutated in human cancers. Ras proteins are encoded by three ubiquitously expressed genes: HRAS, KRAS, and NRAS. HRAS, KRAS, and NRAS are GTPases that function as molecular switches regulating pathways responsible for proliferation and cell survival. Ras proteins are tightly regulated by guanine nucleotide exchange factors (GEFs) promoting GDP disassociation and GTP binding and GTP- ase activating proteins (GAPs) that stimulate the intrinsic GTPase activity of Ras to switch off signaling.
  • GEFs guanine nucleotide exchange factors
  • GAPs GTP- ase activating proteins
  • Aberrant Ras function can be associated with hyper-proliferative developmental disorders and cancer, and Ras genes are among the earliest genes mutated in a variety of cancers.
  • Ras isoforms share sequence identity in all the regions responsible for GDP/GTP binding, GTPase activity, and effector interactions suggesting functional redundancy. KRAS mutations are more frequently observed in cancer. Each ITRAS, KRAS, and NRAS isoform can display preferential coupling to particular cancer types.
  • the compounds and methods of the disclosure can target codon 12 mutations. In some embodiments, the compounds and methods of the disclosure can target KRAS codon 12 mutations.
  • the KRAS codon 12 mutation is G12D. In some embodiments, the KRAS codon 12 mutation is G12V. In some embodiments, the compounds and methods of the disclosure can engage KRAS codon 12 mutations with allele-specific target engagement. In some embodiments, the compounds and methods of the disclosure can engage RNA to inhibit translation of KRAS codon 12 mutations. In some embodiments, the compounds and methods of the disclosure can engage DNA to inhibit translation of KRAS codon 12 mutations.
  • ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • RNA 10 - a b a b a b a b a b a b a b a O b a Unless otherwise noted, all C-termini are amidated.
  • b Portions of structure code not encompassed within braces correspond to the PNA SEQ NO provided in this column.
  • c Portion of structure code within braces (e.g., ⁇ PKKKRKV ⁇ "), when present, correspond to SEQ ID NO provided in this column.
  • TABLE 2 a Proteinogenic amino acid residues in compounds provided in TABLE 1 are represented by the following one-letter codes: A: Z-alanine, R: L-arginine, N: /.-asparagine, D: L -aspartic acid, C: L-cysteine, E: L-glutamic acid, Q: L-glutamine, G: glycine, H: L-histidine, I: L-isoleucine, L: L- leucine , K: L-lysine, M: L-methionine, F: L-phenylalanine, P: L-proline, S: L-serine, T: L- threonine, W: L-tryptophan, Y: L-tyrosine, V: L-valine.
  • A Z-alanine
  • R L-arginine
  • N /.-asparagine
  • D L -aspartic acid
  • C L-cysteine
  • the compound as disclosed herein can comprise a nucleic acid structure (e.g., a polynucleotide structure, a peptide nucleic acid (PNA) structure, or a combination thereof) exhibiting specific binding to a polynucleotide sequence of a Ras protein- encoding gene (e.g., HRAS, KRAS, and/or NRAS).
  • the polynucleotide sequence can be a DNA sequence (e.g., a chromosomal DNA sequence) or an RNA (e.g., mRNA) sequence.
  • the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure comprises a gamma peptide nucleic acid residue that bears a hydroxyalkyl substituent.
  • the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a mRNA sequence transcribed from a KRAS gene, wherein the peptide nucleic acid structure comprises at least 13 peptide nucleic acid residues.
  • the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a mRNA sequence transcribed from a KRAS gene, wherein the peptide nucleic acid structure is attached to a sequence of at least 5 amino acid residues.
  • the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure does not comprise a 1,4,7-tris(carboxymethylaza)cyclododecane-10-aza-acetyl group.
  • the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(0)-alkyl; and iii) guani dinoalkyl.
  • the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl.
  • the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH.
  • the sequence of nucleic acids encoding the KRAS gene is an RNA (e.g., mRNA) sequence.
  • the sequence of nucleic acids encoding the KRAS gene is a DNA sequence.
  • FIG. 28 illustrates the structure of Compound 5.
  • FIG. 29 illustrates the structure of Compound 8.
  • FIG. 30 illustrates the structure of Compound 9.
  • FIG. 31 illustrates the structure of Compound 11.
  • FIG. 32 illustrates the structure of Compound 12.
  • FIG. 33 illustrates the structure of Compound 26.
  • FIG. 34 illustrates the structure of Compound 62.
  • FIG. 35 illustrates the structure of Compound 63.
  • FIG. 36 illustrates the structure of Compound 69.
  • FIG. 37 illustrates the structure of Compound 71.
  • FIG. 38 illustrates the structure of Compound 75.
  • FIG. 39 illustrates the structure of Compound 76.
  • FIG. 40 illustrates the structure of Compound 90.
  • FIG. 41 illustrates the structure of Compound 93.
  • the disclosure provides a compound comprising a structure that is:
  • N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R 1 is a hydroxyalkyl group; each R alph a is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, OMe, or NH 2 ;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent;
  • PNA1 is a peptide nucleic acid sequence or absent;
  • PNA2 is a peptide nucleic acid sequence or absent
  • L1 is a linker group or absent
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the disclosure provides a compound comprising a structure that is:
  • N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R 1 is a hydroxyalkyl group; each R alph a is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least half of the R 2 groups in the structure are independently methyl substituted with a heterocycle;
  • C-Terminus is OH, OMe, or NH 2 ;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent;
  • L1 is a linker group or absent;
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the compound interferes with expression of a cancer-causing protein.
  • each R 2 is independently methyl substituted with a heterocycle.
  • the structure is: wherein: the number of units with variables defined independently is at least 11;
  • N -Terminus is H, acyl, a group that together with the nitrogen atom to which /V-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R 1 is a hydroxyalkyl group; each R alph a is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; and
  • C-Terminus is OH, OMe, NH 2 , or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the disclosure provides a compound comprising a structure that is: wherein: the number of units with variables defined independently is at least 3;
  • N-Terminus is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R 1 is a hydroxyalkyl group; each R alpha is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, OMe, or NH 2 ;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent; wherein at least one of PEP 1 and PEP2 is a peptide sequence of at least three amino acid residues,
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent
  • L1 is a linker group or absent
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the number of units with variables defined independently is 17, wherein: a first unit is present or absent, and in the first unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a second unit is present or absent, and in the second unit: R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; and R 2 is a third unit is present, and in the third unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; and R 2 is a fourth unit is present, and in the fourth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; and R 2 is a fifth unit is present, and in the fifth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; and R 2 is a sixth unit is present, and in the sixth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; and R 2 is a seventh unit is present, and in the seventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; and R 2 is an eighth unit is present, and in the eighth unit: a ninth unit is present, and in the ninth unit: a tenth unit is present, and in the tenth unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-l-yl; an eleventh unit is present, and in the eleventh unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-l-yl; a twelfth unit is present, and in the twelfth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; thirteenth unit is present, and in the thirteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; and R 2 is a fourteenth unit is present, and in the fourteenth unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-1-yl; a fifteenth unit is present, and in the fifteenth unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-1-yl; a sixteenth unit is present, and in the sixteenth unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-1-yl; a seventeenth unit is present or absent, and in the seventeenth unit:
  • the number of units with variables defined independently is 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-1-yl; a second unit is present or absent, and in the second unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-1-yl; a third unit is present, and in the third unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-1-yl; a fourth unit is present, and in the fourth unit: R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fifth unit is present, and in the fifth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a sixth unit is present, and in the sixth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a seventh unit is present, and in the seventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; an eighth unit is present, and in the eighth unit: 1 a ninth unit is present, and in the ninth unit: 1 a tenth unit is present, and in the tenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; an eleventh unit is present, and in the eleventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twelfth unit is present, and in the twelfth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a thirteenth unit is present, and in the thirteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl
  • R 2 is a fourteenth unit is present, and in the fourteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl;
  • a fifteenth unit is present, and in the fifteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a sixteenth unit is present, and in the sixteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a seventeenth unit is present or absent, and in the seventeenth unit: 1
  • the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit: R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a second unit is present or absent, and in the second unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a third unit is present or absent, and in the third unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fourth unit is present or absent, and in the fourth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fifth unit is present, and in the fifth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a sixth unit is present, and in the sixth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a seventh unit is present, and in the seventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; and R 2 is an eighth unit is present, and in the eighth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; and R 2 is or a ninth unit is present, and in the ninth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl
  • R 2 is or a tenth unit is present, and in the tenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl;
  • a twelfth unit is present, and in the twelfth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a thirteenth unit is present, and in the thirteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fourteenth unit is present, and in the fourteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fifteenth unit is present or absent, and in the fifteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a sixteenth unit is present or absent, and in the sixteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a seventeenth unit is present or absent, and in the seventeenth unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-l-yl
  • the units with variables defined independently counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, and the seventeenth unit, independently if present, each have -CH 2 OH at R 1 .
  • the units with variables defined independently counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, and the seventeenth unit, independently if present, each have H at R 1 .
  • the units with variables defined independently counting from N-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, and the seventeenth unit, independently if present, each have -CH 2 OH at R 1 .
  • the units with variables defined independently counting from N-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, and the sixteenth unit, independently if present, each have H at R 1 .
  • the units with variables defined independently counting from N-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, and the sixteenth unit, independently if present, each have - CH 2 OH at R 1 .
  • the units with variables defined independently counting fromN-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, and the seventeenth unit, independently if present, each have H at R 1 .
  • the disclosed herein is a compound of the formula above, wherein: in the first unit: R 1 is H or -CH 2 OH; in the second unit: R 1 is H or -CH 2 OH; in the third unit: R 1 is H or -CH 2 OH; in the fourth unit: R 1 is H or -CH 2 OH; in the fifth unit: R 1 is H or - CH 2 OH; in the sixth unit: R 1 is H or -CH 2 OH; in the seventh unit: R 1 is H or -CH 2 OH; in the eighth unit: R 1 is H or -CH 2 OH; in the ninth unit: R 1 is H or -CH 2 OH; in the tenth unit: R 1 is H or -CH 2 OH; in the eleventh unit: R 1 is H or -CH 2 OH, in the twelfth unit: R 1 is H or -CH 2 OH; in the thirteenth unit: R 1 is H or -CH 2 OH; in the thirteenth unit: R 1 is
  • the number of units with variables defined independently is 17, wherein: a first unit is present or absent, and in the first unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; a second unit is present or absent, and in the second unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; O) a third unit is present or absent, and in the third unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; a fourth unit is present or absent, and in the fourth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; ; or a fifth unit is present, and in the fifth unit: R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; O a sixth unit is present, and in the sixth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; and R 2 is a seventh unit is present, and in the seventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; an eighth unit is present, and in the eighth unit: R 2 is a ninth unit is present, and in the ninth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; a tenth unit is present, and in the tenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; an eleventh unit is present, and in the eleventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; O a twelfth unit is present, and in the twelfth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a thirteenth unit is present, and in the thirteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fourteenth unit is present, and in the fourteenth unit: 1 O a fifteenth unit is present or absent, and in the fifteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; a sixteenth unit is present or absent, and in the sixteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl; a seventeenth unit is present or absent, and in the seventeenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-l-yl
  • R 1 is H or -CH 2 OH
  • in the second unit R 1 is H or -CH 2 OH
  • in the third unit R 1 is H or -CH 2 OH
  • in the fourth unit R 1 is H or -CH 2 OH
  • in the fifth unit R 1 is H or -CH 2 OH
  • in the sixth unit R 1 is H or -CH 2 OH
  • in the seventh unit R 1 is H or -CH 2 OH
  • in the eighth unit R 1 is H or -CH 2 OH
  • in the ninth unit R 1 is H or -CH 2 OH
  • in the tenth unit R 1 is H or -CH 2 OH
  • in the eleventh unit R 1 is H or -CH 2 OH
  • in the twelfth unit R 1 is H or -CH 2 OH
  • in the thirteenth unit R 1 is H or -CH 2 OH; in the thirteenth unit: R 1 is H or -CH 2 OH; in the
  • the number of units with variables defined independently is 27, wherein: a first unit is present or absent, and in the first unit:
  • R 1 is H, -CH2OH, or 4-guanidinobut-l-yl; a second unit is present or absent, and in the second unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a third unit is present or absent, and in the third unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fourth unit is present or absent, and in the fourth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fifth unit is present or absent, and in the fifth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a sixth unit is present or absent, and in the sixth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a seventh unit is present or absent, and in the seventh unit: R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; an eighth unit is present or absent, and in the eighth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a ninth unit is present or absent, and in the ninth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a tenth unit is present or absent, and in the tenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; an eleventh unit is present or absent, and in the eleventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twelfth unit is present, and in the twelfth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a thirteenth unit is present, and in the thirteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl;
  • R 2 is a fourteenth unit is present, and in the fourteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fifteenth unit is present, and in the fifteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a sixteenth unit is present, and in the sixteenth unit: 1 a seventeenth unit is present, and in the seventeenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; an eighteenth unit is present, and in the eighteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a nineteenth unit is present, and in the nineteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twentieth unit is present, and in the twentieth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-first unit is present, and in the twenty -first unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-second unit is present or absent, and in the twenty-second unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-third unit is present or absent, and in the twenty-third unit: R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-fourth unit is present or absent, and in the twenty -fourth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-fifth unit is present or absent, and in the twenty-fifth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-sixth unit is present or absent, and in the twenty-sixth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-seventh unit is present or absent, and in the twenty-seventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; [0082] In some embodiments, the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, wherein: a first unit is present or absent, and in the first unit: R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a second unit is present or absent, and in the second unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a third unit is present or absent, and in the third unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fourth unit is present or absent, and in the fourth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fifth unit is present or absent, and in the fifth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a sixth unit is present or absent, and in the sixth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a seventh unit is present or absent, and in the seventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; an eighth unit is present or absent, and in the eighth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a ninth unit is present or absent, and in the ninth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a tenth unit is present or absent, and in the tenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; an eleventh unit is present or absent, and in the eleventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twelfth unit is present, and in the twelfth unit: R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a thirteenth unit is present, and in the thirteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fourteenth unit is present, and in the fourteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a fifteenth unit is present, and in the fifteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl;
  • R 2 is O a sixteenth unit is present, and in the sixteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl
  • R 2 is or a seventeenth unit is present, and in the seventeenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl;
  • O an eighteenth unit is present, and in the eighteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a nineteenth unit is present, and in the nineteenth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; and R 2 is a twentieth unit is present, and in the twentieth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-first unit is present, and in the twenty -first unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-second unit is present or absent, and in the twenty-second unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-third unit is present or absent, and in the twenty-third unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-fourth unit is present or absent, and in the twenty -fourth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; and R 2 is a twenty-fifth unit is present or absent, and in the twenty-fifth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-sixth unit is present or absent, and in the twenty-sixth unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl; a twenty-seventh unit is present or absent, and in the twenty-seventh unit:
  • R 1 is H, -CH 2 OH, or 4-guanidinobut-1-yl;
  • the units with variables defined independently counting fromN-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the eighteenth unit, the nineteenth unit, the twentieth unit, the twenty-first unit, the twenty- second unit, the twenty -third unit, the twenty-fourth unit, the twenty -fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have -CH 2 OH at R 1 .
  • the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty -first unit, the twenty -third unit, the twenty-fifth unit, and the twenty- seventh unit, independently if present each have -CH 2 OH at R 1 .
  • the units with variables defined independently counting fromN-Terminus , the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty -first unit, the twenty -third unit, the twenty-fifth unit, and the twenty- seventh unit, independently if present, each have H at R 1 .
  • the fourth unit, the eighth unit, the twelfth unit, the sixteenth unit, the twentieth unit, and the twenty -fourth unit each have -CH 2 OH at R 1 .
  • the units with variables defined independently counting fromN-Terminus , the first unit, the second unit, the third unit, the fifth unit, the sixth unit, the seventh unit, the ninth unit, the tenth unit, the eleventh unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the seventeenth unit, the eighteenth unit, the nineteenth unit, the twenty-first unit, the twenty-second unit, the twenty -third unit, the twenty-fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R 1 .
  • the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the eighteenth unit, and the nineteenth unit each have -CH 2 OH at R 1 .
  • the units with variables defined independently counting fromN-Terminus , the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the twentieth unit, the twenty -first unit, the twenty-second unit, the twenty -third unit, the twenty-fourth unit, the twenty-fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R 1 .
  • the units with variables defined independently counting fromN-Terminus , the first unit, the third unit, the fourth unit, the fifth unit, the seventh unit, the eighth unit, the ninth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty- first unit, the twenty-third unit, the twenty-fourth unit, the twenty-fifth unit, and the twenty- seventh unit, independently if present, each have -CH 2 OH at R 1 .
  • the fourth unit, the eighth unit, the twelfth unit, the sixteenth unit, the seventeenth unit, the twentieth unit, and the twenty-fourth unit each have -CH 2 OH atR 1 .
  • the units with variables defined independently counting fromN-Terminus , the first unit, the second unit, the third unit, the fifth unit, the sixth unit, the seventh unit, the ninth unit, the tenth unit, the eleventh unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the eighteenth unit, the nineteenth unit, the twenty -first unit, the twenty-second unit, the twenty -third unit, the twenty -fifth unit, the twenty-sixth unit, and the twenty- seventh unit, independently if present, each have H at R 1 .
  • the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the eighteenth unit, and the nineteenth unit each have -CH 2 OH at R 1 .
  • the units with variables defined independently counting fromN-Terminus , the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the twentieth unit, the twenty -first unit, the twenty-second unit, the twenty -third unit, the twenty -fourth unit, the twenty-fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R 1 .
  • R 1 is H or -CH 2 OH
  • in the second unit R 1 is H or -CH 2 OH
  • in the third unit R 1 is H or -CH 2 OH
  • in the fourth unit R 1 is H or -CH 2 OH
  • in the fifth unit R 1 is H or -CH 2 OH
  • in the sixth unit R 1 is H or -CH 2 OH
  • in the seventh unit R 1 is H or -CH 2 OH
  • in the eighth unit R 1 is H or -CH 2 OH
  • in the ninth unit R 1 is H or -CH 2 OH
  • in the tenth unit R 1 is H or -CH 2 OH
  • in the eleventh unit R 1 is H or -CH 2 OH
  • in the twelfth unit R 1 is H or -CH 2 OH
  • in the thirteenth unit R 1 is H or -CH 2 OH; in the thirteenth unit: R 1 is H or -CH 2 OH; in the
  • At least a third of the R 2 groups in the structure are methyl substituted with a heterocycle. In some embodiments, at least half of the R 2 groups in the structure are methyl substituted with a heterocycle.
  • the heterocycles of the R 2 groups are nucleobases or analogues of nucleobases. In some embodiments, at least one of the heterocycles of the R 2 groups is a divalent nucleobase. In some embodiments, the heterocycles of the R 2 groups are divalent nucleobases. In some embodiments, the heterocycles of the R 2 groups are each independently:
  • PEP1 is absent. In some embodiments, PEP1 is the peptide sequence. In some embodiments, the peptide sequence of PEP 1 is a nuclear localization sequence. In some embodiments, PEP1 is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1). In some embodiments, PEP1 is Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2). In some embodiments, PEP1 is -Ala-Lys-Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 77).
  • PEP1 is -Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 78). In some embodiments, PEP1 is -Arg-Arg-. In some embodiments, PEP1 is -Arg-Phe-Gln-Ile-Leu-Tyr-Arg- (SEQ ID NO: 86). In some embodiments, PEP2 is absent. In some embodiments, PEP2 is the peptide sequence. In some embodiments, the peptide sequence of PEP2 is a nuclear localization sequence. In some embodiments, PEP2 is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1).
  • PEP2 is Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2). In some embodiments, PEP2 is -Arg-Arg-. In some embodiments, PEP2 is -Arg-Phe-Gln-Ile-Leu-Tyr- Arg- (SEQ ID NO: 86).
  • SOL1 is absent. In some embodiments, SOL1 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL1 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL1 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOL1 is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL1 is a polyethyleneglycol group. In some embodiments, the water- solubilizing group of SOL1 is -Arg-Arg-NH(CH 2 ) 2 C(0)-Arg-Arg-. [00103] In some embodiments, the sequence of nucleic acids encoding the KRAS gene is a mRNA sequence. In some embodiments, the sequence of nucleic acids encoding the KRAS gene is a DNA sequence.
  • the water-solubilizing group of SOL1 is a group of formula:
  • R 1a is H, alkyl, or a nitrogen atom protecting group
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group
  • R 4a is H, alkyl, or a nitrogen atom protecting group
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), orN(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
  • the water-solubilizing group of SOLI is a group of formula: wherein p is an integer that is 1-1,000. In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8.
  • p is an integer that is 7. [00106] In some embodiments, SOL2 is absent. In some embodiments, SOL2 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL2 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL2 is a polyethyleneglycol group.
  • the water- solubilizing group of SOL2 is -Arg-Arg-NH(CH 2 ) 2 C(0)-Arg-Arg-. [00107] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
  • R 1a is H, alkyl, or a nitrogen atom protecting group
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group
  • R 4a is H, alkyl, or a nitrogen atom protecting group
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), orN(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
  • the water-solubilizing group of SOL2 is a group of formula: wherein p is an integer that is 1-1,000. In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8.
  • p is an integer that is 7.
  • PNA1 is the peptide nucleic acid sequence.
  • PNA2 is the peptide nucleic acid sequence.
  • L1 is the linker group.
  • the linker group of LI is cleavable.
  • the linker group of L1 is non-cleavable.
  • the linker group of L1 is a peptide sequence.
  • the linker group of L1 is a polyamine sequence.
  • the linker group of L1 is a polyamide sequence.
  • the linker group of L1 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L1 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L1 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L1 is a residue of oxalic acid. In some embodiments, the linker group of L1 is a residue of succinic acid. In some embodiments, the linker group of L1 is a peptide sequence that is -Glu-Val-Citrulline-.
  • the linker group of L1 is - NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L1 is -NHCH(C00H)C(CH 3 )2S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L1 is -Arg-NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L1 is - NH(CH 2 ) 5 C(0)-.
  • the linker group of L1 is -NH(CH 2 ) 2 C(0)-Arg- NH(CH 2 )5C(0)NH(CH 2 )2C(0)-. In some embodiments, the linker group of L1 is - NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • L2 is the linker group. In some embodiments, the linker group of L2 is cleavable. In some embodiments, the linker group of L2 is non-cleavable. In some embodiments, the linker group of L2 is a peptide sequence. In some embodiments, the linker group of L2 is a polyamine sequence. In some embodiments, the linker group of L2 is a polyamide sequence. In some embodiments, the linker group of L2 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L2 is a residue of an omega-amino caproic acid.
  • the linker group of L2 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L2 is a residue of oxalic acid. In some embodiments, the linker group of L2 is a residue of succinic acid. In some embodiments, the linker group of L2 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L2 is - NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 )2CH(NH 2 )C(0)-.
  • the linker group of L2 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L2 is -Arg-NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L2 is - NH(CH 2 )5C(0)-. In some embodiments, the linker group of L2 is -NH(CH 2 ) 2 C(0)-Arg- NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L2 is - NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • L3 is the linker group. In some embodiments, the linker group of L3 is cleavable. In some embodiments, the linker group of L3 is non-cleavable. In some embodiments, the linker group of L3 is a peptide sequence. In some embodiments, the linker group of L3 is a polyamine sequence. In some embodiments, the linker group of L3 is a polyamide sequence. In some embodiments, the linker group of L3 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L3 is a residue of an omega-amino caproic acid.
  • the linker group of L3 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L3 is a residue of oxalic acid. In some embodiments, the linker group of L3 is a residue of succinic acid. In some embodiments, the linker group of L3 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L3 is -NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-.
  • the linker group of L3 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L3 is -Arg-NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L3 is - NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L3 is -NH(CH 2 ) 2 C(0)-Arg- NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L3 is - NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • L4 is the linker group. In some embodiments, the linker group of L4 is cleavable. In some embodiments, the linker group of L4 is non-cleavable. In some embodiments, the linker group of L4 is a peptide sequence. In some embodiments, the linker group of L4 is a polyamine sequence. In some embodiments, the linker group of L4 is a polyamide sequence. In some embodiments, the linker group of L4 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L4 is a residue of an omega-amino caproic acid.
  • the linker group of L4 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L4 is a residue of oxalic acid. In some embodiments, the linker group of L4 is a residue of succinic acid. In some embodiments, the linker group of L4 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L4 is -NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-.
  • the linker group of L4 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L4 is -Arg-NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L4 is - NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L4 is -NH(CH 2 ) 2 C(0)-Arg- NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L4 is - NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • L5 is the linker group. In some embodiments, the linker group of L5 is cleavable. In some embodiments, the linker group of L5 is non-cleavable. In some embodiments, the linker group of L5 is a peptide sequence. In some embodiments, the linker group of L5 is a polyamine sequence. In some embodiments, the linker group of L5 is a polyamide sequence. In some embodiments, the linker group of L5 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L5 is a residue of an omega-amino caproic acid.
  • the linker group of L5 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L5 is a residue of oxalic acid. In some embodiments, the linker group of L5 is a residue of succinic acid. In some embodiments, the linker group of L5 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L5 is -NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-.
  • the linker group of L5 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L5 is -Arg-NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L5 is - NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L5 is -NH(CH 2 ) 2 C(0)-Arg- NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L5 is - NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • L6 is the linker group. In some embodiments, the linker group of L6 is cleavable. In some embodiments, the linker group of L6 is non-cleavable. In some embodiments, the linker group of L6 is a peptide sequence. In some embodiments, the linker group of L6 is a polyamine sequence. In some embodiments, the linker group of L6 is a polyamide sequence. In some embodiments, the linker group of L6 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L6 is a residue of an omega-amino caproic acid.
  • the linker group of L6 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L6 is a residue of oxalic acid. In some embodiments, the linker group of L6 is a residue of succinic acid. In some embodiments, the linker group of L6 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L6 is -NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-.
  • the linker group of L6 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L6 is -Arg-NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L6 is - NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L6 is -NH(CH 2 ) 2 C(0)-Arg- NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L6 is - NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • the structure is: wherein: the number of units with variables defined independently is at least 3;
  • N-Terminu s is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H; each R alph a is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; and
  • C-Terminus is OH, OMe, NH 2 , or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the structure is:
  • the structure is:
  • the disclosure provides a compound comprising a structure that is:
  • N-Terminus is H, acyl, a group that together with the nitrogen atom to which A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R 3 is independently a hydroxyalkyl group; each R 4 is independently R 2 ; each R 5 is independently a group that is not hydroxyalkyl; each R 6 is independently R 2 ; each R 7 is independently alkyl that is unsubstituted or substituted or H; each R 8 is independently R 2 , wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; each R alpha1 is independently alkyl that is unsubstituted or substituted or H; each R alpha2 is independently alkyl that is unsubstituted or substituted or H;
  • C-Terminus is OH, OMe, or NH 2
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent
  • L1 is a linker group or absent
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the first number of units with variables defined independently is 3-1,000. In some embodiments, the first number of units with variables defined independently is 3-100. In some embodiments, the first number of units with variables defined independently is 3-50. In some embodiments, the first number of units with variables defined independently is 3,
  • the first number of units with variables defined independently is at least 11. In some embodiments, the first number of units with variables defined independently is 11-
  • the first number of units with variables defined independently is
  • the first number of units with variables defined independently is 11-50. In some embodiments, the first number of units with variables defined independently is
  • the second number of units with variables defined independently is 3-1,000. In some embodiments, the second number of units with variables defined independently is 3-100. In some embodiments, the second number of units with variables defined independently is 3-50. In some embodiments, the second number of units with variables defined independently is 3, 4,
  • the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
  • the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
  • the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
  • the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
  • the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, or 10.
  • the third number of units with variables defined independently is 3-1,000. In some embodiments, the third number of units with variables defined independently is 3-100. In some embodiments, the third number of units with variables defined independently is 3-50. In some embodiments, the third number of units with variables defined independently is
  • the third number of units with variables defined independently is at least 11. In some embodiments, the third number of units with variables defined independently is 11-1,000. In some embodiments, the third number of units with variables defined independently is 11-100. In some embodiments, the third number of units with variables defined independently is 11-50. In some embodiments, the third number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, each R 3 is hydroxymethyl. In some embodiments, each R 5 is H.
  • the disclosure provides a compound comprising a repeating unit of formula: wherein: each R 1 is independently a hydroxyalkyl group; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R 3 is independently a group that is not hydroxyalkyl; each R 4 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R alpha1 is independently alkyl that is unsubstituted or substituted or H; and each R alpha2 is independently alkyl that is unsubstituted or substituted or H, wherein the repeating unit occurs at least twice consecutively in the compound.
  • the disclosure provides a compound comprising: 1) a region that comprises a structure that interferes with expression of a cancer-causing protein; and 2) connected to the region that comprises the structure that interferes with expression of the cancer-causing protein, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula: or an ionized form thereof, wherein:
  • R 1 is H, alkyl, or a nitrogen atom protecting group
  • R 2 is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3 is H, alkyl, or a nitrogen atom protecting group
  • R 4 is H, alkyl, or a nitrogen atom protecting group
  • R 5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the cancer-causing protein is H-ras, K-ras, or N-ras. In some embodiments, the cancer-causing protein is mutant K-ras. In some embodiments, the cancer-causing protein is G12D K-ras. In some embodiments, the cancer-causing protein is G12V K- ras. In some embodiments, the cancer-causing protein is G12C K-ras.
  • the region that comprises the structure that interferes with expression of the cancer-causing protein binds to a nucleic acid sequence encoding a cancer gene. In some embodiments, the region that comprises the structure that interferes with expression of the cancer-causing protein binds to a mRNA sequence transcripted from a cancer gene. In some embodiments, the region that comprises the structure that interferes with expression of the cancer-causing protein binds to a mRNA sequence that encodes the cancer- causing protein. In some embodiments, the structure that interferes with expression of the cancer-causing protein is a peptide nucleic acid sequence.
  • the disclosure provides a compound comprising:
  • a compound comprising a repeating unit, wherein the repeating unit comprises: a) a guanidino group; b) a nitrogen atom that is bound to a -C(O)Me group and a -CH 2 C(O)- group; and c) a chain of carbon atoms, wherein the guanidino group is attached to the chain of carbon atoms at a first point of attachment; wherein the nitrogen atom is attached to the chain of carbon atoms at a second point of attachment; and wherein the first point of attachment and the second point of attachment are separated by 3-12 carbon atoms, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the disclosure provides a compound comprising:
  • R 1 is H, alkyl, or a nitrogen atom protecting group
  • R 2 is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3 is H, alkyl, or a nitrogen atom protecting group
  • R 4 is H, alkyl, or a nitrogen atom protecting group
  • R 5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), or N(Pg N );
  • E 1 is a chemical moiety
  • E 2 is a chemical moiety
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
  • p is an integer that is 1-1,000, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the present disclosure provides a peptide nucleic acid comprising a plurality of consecutive peptide nucleic acid monomers, wherein each peptide nucleic monomer of the plurality of consecutive peptide nucleic acid monomers comprises a gamma substituent, wherein each gamma substituent is independently hydroxyalkyl.
  • each gamma substituent is independently hydroxymethyl, 2-hydroxyeth-1-yl, 3- hydroxyprop-1-yl, or 4-hydroxybut-1-yl.
  • each gamma substituent is hydroxymethyl.
  • each gamma substituent is hydroxymethyl and the gamma carbon atom has a R-configuration.
  • a C-terminus of the peptide nucleic acid is ami dated.
  • the present disclosure provides a compound that comprises a first peptide nucleic monomer that has a gamma substituent, wherein the first peptide nucleic acid monomer is linked via peptide bond to a second peptide nucleic acid monomer that does not have a gamma substituent, wherein the second peptide nucleic acid monomer is linked via a peptide bond to a third peptide nucleic acid monomer that has a gamma substituent, wherein the third peptide nucleic acid monomer is linked via a peptide bond to a fourth peptide nucleic acid monomer that does not have a gamma substituent.
  • each gamma substituent is independently hydroxyalkyl. In some embodiments, each gamma substituent is independently hydroxymethyl, n-hydroxy ethyl, or n-hydroxybutyl. In some embodiments, each gamma substituent is hydroxymethyl. In some embodiments, each gamma substituent is hydroxymethyl and the gamma carbon atom has a R-configuration.
  • the present disclosure provides a compound that comprises a peptide nucleic acid domain, wherein the peptide nucleic acid domain comprises a first peptide nucleic monomer that has a gamma substituent, wherein the first peptide nucleic acid monomer is linked via peptide bond to a second peptide nucleic acid monomer that does not have a gamma substituent, wherein the second peptide nucleic acid monomer is linked via a peptide bond to a third peptide nucleic acid monomer that has a gamma substituent, wherein the third peptide nucleic acid monomer is linked via a peptide bond to a fourth peptide nucleic acid monomer that does not have a gamma substituent.
  • each gamma substituent is independently hydroxyalkyl. In some embodiments, each gamma substituent is independently hydroxymethyl, 2-hydroxyeth-1-yl, 3-hydroxyprop-1-yl, or 4-hydroxybut-1-yl. In some embodiments, each gamma substituent is hydroxymethyl. In some embodiments, each gamma substituent is hydroxymethyl and the gamma carbon atom has a R-configuration. In some embodiments, the peptide nucleic acid domain i , wherein each of B v and B u are independently nucleobases, and q is from 2 to about 30.
  • the compound further comprises a peptide domain, wherein the N-terminal end of the peptide domain is linked to the C-terminal end of the peptide nucleic acid domain via a peptide bond, wherein the peptide domain has a sequence according to SEQ ID NO 1.
  • the C-terminus of the compound is amidated.
  • the C-terminus of the compound is the C-terminus of the peptide domain.
  • the compound further comprises a polyguanidyl domain linked to the peptide nucleic acid domain, wherein the polyguanidyl domain comprises a peptide nucleic acid backbone substituted with a plurality of guani dinoalkyl moieties.
  • the N-terminal end of the peptide nucleic acid domain is linked to the C-terminal end of the peptide nucleic acid of the polyguanidyl domain via a peptide bond.
  • each R d is independently a guanidinoalkyl moiety of the plurality of guanidinoalkyl moieties; each R e is independently alkyl or acyl; and z is from 2 to about 30.
  • each R d is independently 5- guanidino-pent-1-yl, 4-guanidino-but-l-yl, 3-guanidino-prop-1-yl, or 2-guanidino-ethyl-1-yl.
  • each R d is 4-guanidino-but-l-yl.
  • each R e is independently acetyl, propanoyl, or butanoyl. In some embodiments, each R e is acetyl. In some embodiments, z is from 5-12. In some embodiments, z is 7.
  • FIG. 26 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e g. natural, modified, or non-natural nucleobases), or hydrogen.
  • R is a nucleobase (e g. natural, modified, or non-natural nucleobases), or hydrogen.
  • One or more oligonucleotide residues of a compound of the disclosure may be independently replaced with a residue comprising an alternative oligonucleotide backbone bearing an identical nucleobase.
  • Nonlimiting examples of oligonucleotide backbones suitable for use in the present disclosure include phosphorothioate deoxyribonucleic acid (PS-DNA), boranophosphate DNA, alpha-, beta- constrained nucleic acid ( ⁇ , ⁇ -CnA), 2'-methoxyribonucleic acid (2'-OMe-RNA), 2'- fluororibonucleic acid (2'-F-RNA), 2'-fluoroarabinonucleic acid (2 ' -F-ANA), sulfonyl-linked nucleic acid, methylene(methylimino) (MMI) linked, formacetal-linked nucleic acid, threose nucleic acid (TNA), 2'-methoxyribonucleic acid (2'-OMe-RNA), 2 ' -O-(2- methoxyethyl)ribonucleic acid (2'-MOE-RNA), unlocked nucleic acid (UNA), 2'-O,4'-C-
  • a compound of the disclosure can be conjugated to one or more polypeptides, such as a cell penetrating peptide, nuclear localization sequence, or other polypeptide that can facilitate uptake or cellular intake.
  • polypeptides such as a cell penetrating peptide, nuclear localization sequence, or other polypeptide that can facilitate uptake or cellular intake.
  • cell- penetrating peptides include SV40 NLS (SEQ ID NO: 1: PKKKRKV), c-Myc NLS (SEQ ID NO: 2: PAAKRVKLD), nuleoplasmin (SEQ ID NO.
  • LRRERQ SRLRRERQ SR LRRERQ SRLRRERQ SR
  • DPV15b SEQ ID NO: 18: GAYDLRRRERQ SRLRRRERQSR
  • HIV-1 Tat SEQ ID NO: 19: RKKRRQRRR
  • FHV coat SEQ ID NO: 20: RRRRNRTRRNRRRVR
  • HIV-1 Rev SEQ ID NO: 21: TRQARRNRRRRWRERQR
  • HTLV- II Rex SEQ ID NO: 22: TRRQRTRRARRNR
  • BMV Gag SEQ ID NO: 23: KMTRAQRRAAARRNRWTAR, P22 N (SEQ ID NO: 24 NAKTRRHERRRKLAIER), ⁇ N(1- 22) (SEQ ID NO: 25: MDAQTRRRERRAEKQAQWKAAN), ⁇ 21N(12-29) (SEQ ID NO: 26:
  • Yeast Prp6 SEQ ID NO: 27: TRRNKRNRIQEQLNRK
  • Protamine 1 SEQ ID NO: 28: PRRRRS S SRP VRRRRRPRV SRRRRRRGGRRRR
  • Human cJun SEQ ID NO: 29: RIKAERKRMRNRIAASKSRKRKLERIAR
  • Human cFos SEQ ID NO: 30: KRRIRRERNKMAAAKSRNRRRELTDT
  • Yeast GCN4 SEQ ID NO: 31 : KRARNTEAARRSRARKLQRMKQ
  • Penetratin SEQ ID NO: 32:
  • SEQ ID NO: 40 RRIRPRPPRLPRPRPRPRPLPFPRPG
  • S413-PVrev SEQ ID NO: 41: ALWKTLLKKVLKAPKKKRKV
  • HRSV SEQ ID NO: 42: RRIPNRRPRR
  • L-2 SEQ ID NO: 43: HARIKPTFRRLKWKYKGKFW
  • Melittin SEQ ID NO: 44: GIGAVLKVLTTGLPALISWIKRKRQQ
  • SynB1 SEQ ID NO: 45: RGGRLSYSRRRFSTSTGR
  • IVV-14 SEQ ID NO: 46: KLWMRWY SPTTRRY G
  • AIP6 SEQ ID NO: 47: RLRWR
  • CAYH SEQ ID NO: 48: CAYHRLRRC
  • SVM4 SEQ ID NO:
  • SVM3 SEQ ID NO: 50: KGTYKKKLMRIPLKGT
  • SVM2 SEQ ID NO: 51: RASKRDGSWVKKLHRILE
  • Buforin 2 SEQ ID NO: 52: TRS SRAGLQWPVGRVHRLLRK
  • SVM1 SEQ ID NO: 53: FKIYDKKVRTRVVKH
  • SAP SEQ ID NO: 54: VRLPPPVRLPPPVRLPPP
  • 435b SEQ ID NO: 55: GPFHFYQFLFPPV
  • Peptl SEQ ID NO: 56: PLILLRLLRGQF
  • YTA2 SEQ ID NO: 57
  • YT AIAW VK AFIRKLRK Pep-1
  • Pep-1 SEQ ID NO: 58: KET WET WWTEW S QPKKRK V
  • EB-1 SEQ ID NO: 59: LIRE W SHLIHIWF QNRRLKWKKK
  • Pyrrho-coricin SEQ ID NO: 60: VDKGSYLPRPTPPRPIYNRN
  • 439a SEQ ID NO: 61: GSPW GLQHHPPRT
  • MAP SEQ ID NO: 62: KLALKALKALKAALKLA
  • Bip (1) SEQ ID NO: 63: IPALK
  • Bip (2) SEQ ID NO: VPALR
  • pVEC SEQ ID NO: 65: LLIILRRRIRKQAHAFISK
  • YTA4 SEQ ID NO: 66: IAWVKAFIRKLRKGPLG
  • K-FGF+NLS SEQ ID NO: 67:
  • a compound of the disclosure is conjugated to a peptide that targets specific tissue, such as a muscle-targeting peptides.
  • Suitable muscle targeting peptides can include, for example, MSP1 (SEQ ID NO: 77: AKASSLNIA), MSP2 (SEQ ID NO: 78: ASSLNIA), and A2G80 (SEQ ID NO: 79: VQLRNGFPYFSY).
  • a compound of the disclosure is conjugated to a peptide that targets brain tissue.
  • Suitable brain targeting peptides can include, for example, SEQ ID NO: 142: C(&)LS SRLD AC(&), SEQ ID NO: 143: C(&)AGALC(&)Y, SEQ ID NO: 144: C(&)LEVSRKNC(&), SEQ ID NO: 145: C(&)TSTSAPYC(&), SEQ ID NO: 146: c(&)MPRLRGC(&), and SEQ ID NO: 147: TGNYKALHPHNG.
  • peptides suitable for conjugation with a compound of the disclosure include transferrin receptor binders, such as THR (SEQ ID NO: 80: THRPPMWSPVWP) and HAI (SEQ ID NO: 81: HAIYPRH), as well as peptides that bind transferrin receptor-transferrin complex, such as CRT (SEQ ID NO: 82: C(&)RTIGPSVC(&)).
  • transferrin receptor binders such as THR (SEQ ID NO: 80: THRPPMWSPVWP) and HAI (SEQ ID NO: 81: HAIYPRH)
  • CRT SEQ ID NO: 82: C(&)RTIGPSVC(&)
  • Retro-enantio analogues of any peptide disclosed herein are also suitable for conjugation to a compound of the present disclosure.
  • a retro-enantio analogue can mimic the natural function of a corresponding parent peptide while exhibiting increased resistance to degradation.
  • a retro-enantio analogue includes a peptide analogue where, relative to a parent peptide, both the linear peptide sequence and alpha-carbon chirality are inverted.
  • a retro-enantio analogue of THR (SEQ ID NO: 80: THRPPMWSPVWP) can be THRre (SEQ ID NO: 83: pwvpswmpprht), and a retro-enantio analogue of HAI (SEQ ID NO: 81: HAIYPRH) can be HAIre (SEQ ID NO: 84: hrpyiah), where lowercase one letter codes denote D-amino acid residues.
  • Enantiomers of any peptide disclosed herein are also contemplated, which enantiomers can include, for example, D-THR (SEQ ID NO: 85: thrppmwspvwp).
  • peptides suitable for conjugation with a compound of the disclosure include peptides consisting of or comprising sequences such as RFQILYR (SEQ ID NO: 86), RYQFLIR (SEQ ID NO: 87), RIQFLIR (SEQ ID NO: 88), RRWQW (SEQ ID NO: 89), GWWG (SEQ ID NO: 90), GFWFG (SEQ ID NO: 91), and GRKKRRQRRRPQ (SEQ ID NO: 92).
  • Peptides comprising repeating units of charged residues are also contemplated, such as sequences comprising repeating units of contiguous arginine and glycine residues, such as (RG) e where e is from 1 to 50 (SEQ ID NO: 138) (e g. SEQ ID NO: 93: RGRGRGRGRGRGRGRG), polyarginine comprising from 2 to 100 contiguous arginine residues (SEQ ID NO: 139), (e.g. SEQ ID NO:
  • a compound of the disclosure is conjugated to a sequence derived from HIV-1 Tat, which can include, for example, RKKRRQRRR (SEQ ID NO: 19), YGRKKRRQRRR (SEQ ID NO: 149), and GRKKRRQ (SEQ ID NO: 150).
  • sequence variants of the sequences described herein are contemplated.
  • a variant typically differs from a sequence specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions.
  • Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of sequences of the disclosure and evaluating one or more biological activities of the compounds as described herein.
  • Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid and/or nucleic acid sequences of the compound. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., modulation of a genetic target.
  • Percent (%) sequence identity with respect to a reference polypeptide or oligonucleotide sequence is the percentage of amino acid residues, nucleoside residues, and/or nucleoside analogue residues in a candidate sequence that are identical with residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.
  • Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • the degree of sequence identity between two sequences can be determined, for example, by comparing the two sequences using computer programs designed for this purpose, such as global or local alignment algorithms.
  • Non-limiting examples include BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), BLASTp, BLASTn, Clustal W, MAFFT, Clustal Omega, AlignMe, Praline, GAP, BESTFIT, Needle (EMBOSS), Stretcher (EMBOSS), GGEARCH2SEQ, Water (EMBOSS), Matcher (EMBOSS), LALIGN, SSEARCH2SEQ, or another suitable method, software or algorithm.
  • a global alignment algorithm such as a Needleman and Wunsch algorithm, can be used to align two sequences over their entire length, maximizing the number of matches and minimizes the number of gaps. Default settings can be used.
  • % sequence identity values can be generated using the sequence comparison computer program ALIGN-2.
  • the ALIGN-2 program can be compiled for use on a UNIX operating system, including digital UNIX V4.0D. Sequences that can be compared by these algorithms include, for example, peptides, oligonucleotides, PNAs, and analogues of any of the foregoing.
  • the percent identity determination can be made based on comparison of the nucleobases or amino acid side chains. Residues in the two molecules being compared can be considered to share identity for the purpose of the percent identity analysis if the residues share a common nucleobase or amino acid side chain even if the residues have non-identical backbone structures. For example, Compound 58 and Compound 59 can be considered to share 100% nucleobase sequence identity.
  • Non-proteogenic acids can include, for example, b-alanine, cystine, cystathionine, lanthionine, t-leucine, norleucine, homonorleucine, ornithine, allothreonine, homocysteine, citrulline, homoserine, isovaline, norvaline, sarcosine, N-ethyl glycine, N-propyl glycine, N-isopropyl glycine, N-methyl alanine, N-ethyl alanine, N-methyl b-alanine, N-ethyl b-alanine, and isoserine.
  • modifications of one or more amino acids of the compounds can be associated with modifications of one or more amino acids of the compounds.
  • modifications include phosphorylation, acylation including acetylation and formylation, glycosylation (including N- linked and O-linked), amidation, hydroxylation, alkylation including methylation and ethylation, ubiquitination, addition of pyrrolidone carboxylic acid, formation of disulfide bridges, sulfation, myristoylation, palmitoylation, isoprenylation, farnesylation, geranylation, glypiation, lipoylation and iodination.
  • nucleobases within a PNA subunit can be naturally occurring or non-naturally occurring.
  • Non-limiting examples of nucleobases include adenine, guanine, thymine, cytosine, uracil, pseudoisocytosine, 2-thiopseudoisocytosine, 5-methylcytosine, 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine (or 2,6-diaminopurine), 2-thiouracil, 2-thiothymine, 2- thiocytosine, 5-chlorouracil, 5-bromouracil, 5-iodouracil, 5-chlorocytosine,5-bromocytosine, 5- iodocytosine, 5-propynyl uracil, 5-propynyl cytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 7-methylguanine, 7-methyladenine,
  • Compounds disclosed herein can comprise divalent nucleobases.
  • a divalent nucleobase can simultaneously bind specifically to two nucleic acid strands, whether or not the two strands are independent strands, two portions of a single strand (e.g., in a hairpin), or contain mismatches in the sense that at one or more positions within the two strands at the site of binding to the genetic recognition reagents, the bases are not able to base pair according to traditional Watson-Crick base pairing (A-T/U, T/U-A, G-C or C-G).
  • Divalent nucleobases can be incorporated into a oligonucleotide analogue backbone such as those described in FIG. 20 (e.g.
  • PNA monomer which can then be incorporated into an oligomer of monomers with a desired sequence of nucleobases.
  • TABLE 3 provides example divalent bases and their binding specificities, where R 1 is hydrogen or a nitrogen protecting group and X is N or CH.
  • Compounds described herein can comprise one or more isotopic substitutions.
  • hydrogen can be in any isotopic form, including 'H (protium), 2 H (D or deuterium), and 3 H (T or tritium).
  • Carbon can be in any isotopic form, including 12 C, 13 C, and 14 C.
  • Oxygen can be in any isotopic form, including 16 O and 18 O.
  • Compounds described herein can comprise one or more asymmetric centers, and can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods including chiral high-performance liquid chromatography (HPLC), selective crystallization as chiral salts, or in the presence of chiral hosts, or from chiral solvents, and through enrichment using enzymes or chemical processes such as dynamic kinetic resolution.
  • HPLC high-performance liquid chromatography
  • a single isomer can be prepared by asymmetric synthesis.
  • the disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, hydrocarbyl groups, acyloxy groups, carbamate groups, amide groups, and ester groups.
  • Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups.
  • An alkyl group can be, for example, a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 ,
  • Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups.
  • Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec- butyl, and t-butyl.
  • Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.
  • Non-limiting examples of alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups.
  • the olefin or olefins of an alkenyl group can be, for example, E , Z, cis, trans, terminal, or exo-methylene.
  • An alkenyl or alkenylene group can be, for example, a C 2 , C 3 , C 4 , Cs, C 6 , C 7 , C 8 , C 9 , C10, C11, C12, C13, C 14 , C15, C16, C17, C18, C19, C20, C21, C22, C23, C 24 , C25,
  • Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups.
  • the triple bond of an alkylnyl or alkynylene group can be internal or terminal.
  • An alkylnyl or alkynylene group can be, for example, a C 2 , C 3 , C 4 , C 5 , C6, C7, C8, C 9 , C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30,
  • a halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
  • a halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms.
  • a halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
  • An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group.
  • An ether or an ether group comprises an alkoxy group.
  • Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
  • An aryl group can be heterocyclic or non-heterocyclic.
  • An aryl group can be monocyclic or polycyclic.
  • An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms.
  • aryl groups include phenyl, toluyl, naphthyl, pyrrdyl, pyridyl, imidazolyl, thiophenyl, and furyl.
  • An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy.
  • An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl.
  • An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyl oxy.
  • a heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom.
  • a heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms.
  • a heterocycle can be aromatic (heteroaryl) or non-aromatic.
  • Non-limiting examples of heterocycles include nucleobases, pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
  • An acyl group can be, for example, a carbonyl group substituted with hydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle.
  • Non-limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxy carbonyl, and ethoxy carbonyl.
  • An acyloxy group can be an oxygen atom substituted with an acyl group.
  • An ester or an ester group comprises an acyloxy group.
  • a non-limiting example of an acyloxy group, or an ester group, is acetate.
  • a carbamate group can be an oxygen atom substituted with a carbamoyl group, wherein the nitrogen atom of the carbamoyl group is unsubstituted, monosub stituted, or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form a heterocycle.
  • a hydrocarbyl group can be any group consisting of carbon and hydrogen atoms, and can include alkyl groups, alkenyl groups, alkynyl groups, and aryl groups.
  • a hydrocaryl group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group.
  • a hydrocarbylcarbonyl group can be a carbonyl group substituted with a hydrocarbyl group, which can be, for example, benzoyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undencanoyl, dodecanoyl, tridencanoyl, myristoyl, pentadecenoyl, palmitoyl, heptadecanoyl, stearoyl, nondecanoyl, arachidoyl, as well as acyl groups derived from saturated, monounsaturated, and polyunsaturated fatty acids, such as myristoleoyl, palmitoleoyl, sapienoyl, oleoyl, elaidoyl, vaccenoyl, l
  • a hydrocaryl carbonyl group can be, for example, a C 2 , C 3 , C 4 , C 5 , C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group.
  • An aminoalkylene group can be an alkyl group substituted with an amino group, such as, for example, aminom ethyl, 2-aminoeth-1-yl, 3-aminoprop-1-yl, 2-aminoprop-1-yl, 4- aminobut-1-yl, 3-aminobut-1-yl, 2-aminobut-1-yl, 5-aminopent-1-yl, 4-aminopent-1-yl, 4- aminopent-1-yl, 3-aminopent-1-yl, 2-aminopent-1-yl, a lysine side chain, or an ornithine side chain.
  • amino group such as, for example, aminom ethyl, 2-aminoeth-1-yl, 3-aminoprop-1-yl, 2-aminoprop-1-yl, 4- aminobut-1-yl, 3-aminobut-1-yl, 2-aminobut-1-yl, 5-aminopent-1-yl, 4-aminopent-1
  • a guanidinoalkylene group can be an alkyl group substituted with a guanidino group, such as, for example, guanidinomethyl, 2-guanidinoeth-1-yl, 3-guanidinoprop-1-yl, 2- guanidinoprop-1-yl, 4-guanidinobut-1-yl, 3-guanidinobut-1-yl, 2-guanidinobut-1-yl, 5- guanidinopenty-1-1, 4-guanidinopent-1-yl, 4-guanidinopent-1-yl, 3-guanidinopent-1-yl, 2- guanidinopent-1-yl, an arginine side chain, or a homoarginine side chain.
  • a guanidino group such as, for example, guanidinomethyl, 2-guanidinoeth-1-yl, 3-guanidinoprop-1-yl, 2- guanidinoprop-1-yl, 4-guanidinobut-1-yl, 3-
  • Polypeptides and proteins disclosed herein can comprise synthetic amino acids in place of one or more naturally-occurring amino acids.
  • Such synthetic amino acids can include, for example, aminocyclohexane carboxylic acid, norleucine, ⁇ -amino n-decanoic acid, homoserine, S-acetylaminomethyl- cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4- chlorophenylalanine, 4-carboxyphenylalanine, ⁇ -phenylserine ⁇ -hydroxyphenylalanine, phenylglycine, ⁇ -naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, 1,2, 3, 4-tetrahydroisoquinoline-3 -carboxylic acid, aminomalonic acid, aminomalonic acid
  • a compound of a disclosure bears one or more nitrogen protecting groups.
  • nitrogen protecting groups include methyl, formyl, ethyl, acetyl, anisyl, benzyl, benzoyl, carbamate, trifluoroacetyl.
  • sooctyI-9-fluorenylmethoxy carbonyl (mio Fmoc), 2,7-dii sooctyl -9-fluorenylmethoxy carbonyl, tetrachiorophthaloyl (TCP), 2-fluoro ⁇ 9- fluorenylmethoxycarbonyl (Fmoc(2F)), 2-[Phenyl(methyl)sulfonio]ethyloxy carbonyl tetrafluoroborate (Pms), ethanesulfbnylethoxycarbonyl (Esc), 2-(4- suifophenylsulfonyl)ethoxycarbonyl (Sps), N,N-dim ethylaniinoxy carbonyl (Draaoc), and p- bromobenzenesulfonyl.
  • TCP tetrachiorophthaloyl
  • Fmoc(2F) 2-fluoro
  • compositions provide the use of pharmaceutically-acceptable salts of any therapeutic compound described herein.
  • Pharmaceutically-acceptable salts include, for example, acid- addition salts and base-addition salts.
  • the acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid.
  • a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt.
  • a pharmaceutically- acceptable salt is an ammonium salt.
  • Metal salts can arise from the addition of an inorganic base to a compound of the disclosure.
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure.
  • the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, N-m ethyl pi peri dine, A-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.
  • an ammonium salt is a triethyl amine salt, a trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-m ethyl morpholine salt, a piperidine salt, an JV-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.
  • Acid addition salts can arise from the addition of an acid to a compound of the present disclosure.
  • the acid is organic.
  • the acid is inorganic.
  • the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, trifluoroacetic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benz
  • the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a trifluoroacetate salt, a mandelate salt, a cinnamate salt, an aspartate salt, a stearate salt, a palmitate salt, a glycolate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate
  • a compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 4
  • the compounds of the disclosure show non-lethal toxicity.
  • Compounds, compositions, and methods of the disclosure can be used to treat or ameliorate a condition of a subject (e.g., a human subject) in need thereof.
  • Compounds, compositions, and methods of the disclosure can be used to modulate expression of a gene (e.g. a disease-causing gene, such as HRAS, KRAS, and/or NRAS) encoding a protein of the Ras subfamily (e.g. H-ras, K-ras, and/or N-ras).
  • a gene e.g. a disease-causing gene, such as HRAS, KRAS, and/or NRAS
  • a compound disclosed herein can preferentially bind a sequence of nucleic acids encoding for a mutant Ras protein, thereby selectively modulating expression of the mutant protein.
  • TABLE 4 provides nonlimiting examples of mutations that can be targeted by a compound of the disclosure, as well as associated conditions or diseases that can be treated by administration of a compound provided herein.
  • a compound of the disclosure is complementary to a nucleic acid sequence comprising a mutation selected from TABLE 4.
  • G12C bronchioloalveolar squamous cell carcinoma ovary carcinoma pancreas ductal carcinoma pancreas PanIN pancreas adenoma pancreas borderline tumor pancreas chronic pancreatitis pancreas hyperplasia prostate adenocarcinoma skin carcinoma small intestine adenocarcinoma stomach adenocarcinoma thyroid carcinoma Mutation Associated Phenotype Mutation Associated Phenotype biliary tract bile duct carcinoma biliary tract bile duct carcinoma gall bladder carcinoma gall bladder carcinoma gall bladder carcinoma colorectal colon adenocarcinoma colorectal colon adenocarcinoma colorectal colon rectal colorectal colon rectal adenocarcinoma adenocarcinoma endometrium carcinoma endometrium carcinoma gastric cancer H/L hematopoietic neoplasm
  • H/L hematopoietic neoplasm H/L lymphoid neoplasm
  • H/L hematopoietic neoplasm H/L lymphoid neoplasm
  • administration of a compound provided herein does not exhibit or substantially does not exhibit immunogenicity. In some embodiments, administration of a compound provided herein does not promote or substantially does not promote generation of neutralizing antibodies, complement factors, pro-inflammatory cytokines, or type 1 interferons upon or after administration of the compound to a subject. In some embodiments, a compound does not activate or substantially does not activate the TLR9 receptor and is not presented or is minimally presented by MHCI or MHCII complexes to the immune system.
  • Compounds provided herein can be locally or systemically administered to a subject in need thereof as a therapeutically-effective amount of a compound that binds to a sequence of nucleic acids encoding a cancer-causing protein (e.g., mutant K-ras).
  • the subject can comprise a bloodstream, a brain, and a blood-brain-barrier.
  • the compound that binds to the repeat codon can enter the brain by passing from the bloodstream through the blood-brain-barrier into the brain.
  • the present disclosure describes the use of a compound and methods of treating a condition.
  • the method can comprise administering to the subject a therapeutically-effective amount of a compound of the disclosure.
  • the condition is a hematologic malignancy, for example, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or multiple myeloma (MM).
  • CMML chronic myelomonocytic leukemia
  • JMML juvenile myelomonocytic leukemia
  • AML acute myeloid leukemia
  • ALL acute lymphocytic leukemia
  • MM multiple myeloma
  • compounds of the disclosure can be used to treat cancer in a subject.
  • a compound of the disclosure can, for example, slow the proliferation of cancer cell lines, or kill cancer cells.
  • cancer that can be treated by a compound of the disclosure include: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas, Burkitt lymphoma, carcinoma of unknown primary origin, central nervous system lymphoma,
  • the compounds of the disclosure can treat a cancer associated with a KRAS mutation.
  • the cancer is cancer of the adrenal gland, autonomic ganglia, biliary tract, bone, breast, central nervous system, cervix, endometrium, hematopoietic/lymphoid, kidney, large intestine, liver, lung, esophagus, ovary, pancreas, prostate, salivary gland, skin, small intestine, stomach, testis, thymus, thyroid, upper aerodigestic tract, or urinary tract.
  • the cancer is cancer of the biliary tract.
  • the cancer is endometrial cancer.
  • the cancer is cancer of the large intestine. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is cancer of the small intestine.
  • the compounds and methods of the disclosure target a cancer with a HRAS mutation.
  • the HRAS mutation is a codon 12 mutation.
  • the HRAS codon 12 mutation is G12A, G12C, G12D, G12R, G12S, or G12V.
  • the HRAS codon 12 mutation is G12V.
  • the HRAS mutation is a codon 13 mutation.
  • the HRAS codon 13 mutation is G13C, G13D, G13R, G13S, or G13V.
  • the HRAS codon 13 mutation is G13R.
  • the HRAS mutation is a codon 61 mutation.
  • the HRAS codon 61 mutation is Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the HRAS codon 61 mutation is Q61R. In some embodiments, the cancer is a dermatological cancer with an HRAS codon mutation. In some embodiments, the cancer is a head and neck cancer with an HRAS codon mutation.
  • the compounds and methods of the disclosure target a cancer with a KRAS mutation.
  • the KRAS mutation is a codon 12 mutation.
  • the KRAS codon 12 mutation is G12A, G12C, G12D, G12R, G12S, or G12V.
  • the KRAS codon 12 mutation is G12D.
  • the KRAS mutation is a codon 13 mutation.
  • the KRAS codon 13 mutation is G13A, G13C, G13D, G13R, G13S, or G13V.
  • the KRAS codon 13 mutation is G13D.
  • the KRAS mutation is a codon 61 mutation.
  • the KRAS codon 61 mutation is Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R.
  • the KRAS codon 61 mutation is Q61H.
  • the cancer is pancreatic carcinoma with a KRAS codon mutation.
  • the cancer is colorectal cancer with a KRAS codon mutation.
  • the cancer is a lung cancer with a KRAS codon mutation.
  • the compounds and methods of the disclosure target a cancer with a NRAS mutation.
  • the NRAS mutation is a codon 12 mutation.
  • the NRAS codon 12 mutation is G12A, G12C, G12D, G12R, G12S, or G12V.
  • the NRAS codon 12 mutation is G12D.
  • the NRAS mutation is a codon 13 mutation.
  • the NRAS codon 13 mutation is G13A, G13C, G13D, G13R, G13S, or G13V.
  • the NRAS codon 13 mutation is G13D.
  • the NRAS mutation is a codon 61 mutation.
  • the NRAS codon 61 mutation is Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R.
  • the NRAS codon 61 mutation is Q61R.
  • the cancer is a melanoma with an NRAS codon mutation.
  • the cancer is a hematopoietic malignancy with an NRAS codon mutation.
  • a compound of the disclosure binds to the nucleobase that corresponds to the nucleotide polymorphism of the non-wild type RAS gene of a subject. In some embodiments, a compound of the disclosure binds to the nucleobase that corresponds to the nucleotide polymorphism of the non-wild type HRAS gene of a subject. In some embodiments, a compound of the disclosure binds to the nucleobase that corresponds to the nucleotide polymorphism of the non-wild type KRAS gene of a subject.
  • a compound of the disclosure binds to the nucleobase that corresponds to the nucleotide polymorphism of the non-wild type NRAS gene of a subject.
  • a compound of the disclosure binds to an RNA (e.g., mRNA) sequence transcribed from a non-wild type RAS gene.
  • a compound of the disclosure binds to an mRNA sequence transcribed from a non-wild type KRAS gene.
  • a compound of the disclosure binds to an mRNA sequence transcribed from a non-wild type HRAS gene.
  • a compound of the disclosure binds to an mRNA sequence transcribed from a non-wild type NRAS gene.
  • a compound of the disclosure binds to a DNA sequence encoding a cancer gene. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a cancer-causing protein. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a non-wild type RAS gene. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a non-wild type KRAS gene. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a non-wild type HRAS gene. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a non-wild type NRAS gene.
  • administration of a compound of the disclosure does not exhibit immunogenicity. In some embodiments, administration of a compound of the disclosure does not promote generation of neutralizing antibodies, complement factors, pro-inflammatory cytokines, or type 1 interferons upon or after administration of the compound to a subject. In some embodiments, the compounds do not activate the TLR9 receptor and are not presented in MHCI or MHCII complexes to the immune system.
  • the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm 3 to about 10 mm 3 ; on day 5 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm 3 to about 10 mm 3 ; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 360
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm 3 to about 10 mm 3 ; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm 3 to about 120 mm 3 , and a mean tumor volume size in the test group is observed to be from about 80 mm 3 to about 120 mm 3 ; on day 5 of the study, a mean tumor volume size in the control group is determined to be from about 210
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm 3 to about 120 mm 3 , and a mean tumor volume size in the test group is observed to be from about 80 mm 3 to about 120 mm 3 ; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm 3 to about 120 mm 3 , and a mean tumor volume size in the test group is observed to be from about 80 mm 3 to about 120 mm 3 ; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 14
  • the compound is a DNA binding agent.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the KRAS gene, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the KRAS gene.
  • the peptide nucleic acid sequence is complementary to the nonwild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene.
  • the peptide nucleic acid sequence is complementary to the nonwild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism.
  • the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the gene.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a DNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence. [00210] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T).
  • the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound preferentially binds to the mRNA sequence transcribed from the non- wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the nonwild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism.
  • the compound reduces expression of the mutant protein by preferentially binding to the non-wild type gene over the wild-type gene. In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence transcribed from the non-wild type gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the compound reduces transcription of the non-wild type KRAS gene. In some embodiments, the compound reduces translation of the mRNA sequence transcribed from the non- wild type gene.
  • the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma.
  • the human cancer associated with the non-wild type KRAS gene is pancreatic cancer. In some embodiments, the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II.
  • the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A).
  • the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the nonwild type K-ras protein is K-ras G12C.
  • the mice are SCID mice.
  • the compound has the formula: wherein each B is independently the nucleobase of the plurality of nucleobase-bearing side chains, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, thymine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, adenine, adenine, adenine, or a pharmaceutically acceptable salt or ionized form thereof.
  • the compound has the formula: wherein each of B 1 and B 2 is independently the nucleobase of the plurality of nucleobase-bearing side chains, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: thymine, guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, adenine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, or a pharmaceutically acceptable salt or ionized form thereof Oncogenic Signaling.
  • the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid sequence associated with a non-wild type KRAS gene, wherein if, in a study: a) i) a test SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF- II cells by subcutaneous injection, and a tumor having a volume of about 100 mm 3 forms in the test SCID mouse; ii) after the tumor forms, the test SCID mouse is dosed intratumorally once per week for three consecutive weeks with the compound in a vehicle at one of 0.3 ⁇ M, 1 ⁇ M, 3 pM, 10 ⁇ M, and 30 ⁇ M; iii) after the three consecutive weeks, the test SCID mouse is monitored until the tumor that forms in the test SCID mouse has a volume of about 1,500 mm 3 ; iv) after the tumor that forms in the test SCID
  • the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be at most about 60% of the amount of phospho- MEK in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be at most about 55% of the amount of phospho- MEK in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be about 40% to about 60% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be about 40% to about 50% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
  • the peptide nucleic acid sequence binds to a mRNA sequence transcribed from the non- wild type KRAS gene.
  • the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid sequence associated with a non-wild type KRAS gene, wherein if, in a study: a) i) a test SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF- II cells by subcutaneous injection, and a tumor having a volume of about 100 mm 3 forms in the test SCID mouse; ii) after the tumor forms, the test SCID mouse is dosed intratumorally once per week for three consecutive weeks with the compound in a vehicle at one of 0.3 ⁇ M , 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, and 30 ⁇ M; iii) after the three consecutive weeks, the test SCID mouse is monitored until the tumor that forms in the test SCID mouse has a volume of about 1,500 mm 3 ; iv) after the tumor that forms in the test SCID
  • the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 40% of the amount of phospho- CREB in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 30% of the amount of phospho- CREB in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be from about 10% to about 30% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be from about 15% to about 25% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
  • the peptide nucleic acid sequence binds to a mRNA sequence transcribed from the non- wild type KRAS gene.
  • the compound has the formula: wherein each B is independently a nucleobase, wherein the peptide nucleic acid sequence has a nucleobase sequence that is guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, thymine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, adenine, adenine, adenine, or a pharmaceutically acceptable salt or ionized form thereof.
  • the compound has the formula: wherein each of B 1 and B 2 is independently a nucleobase, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: thymine, guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, adenine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, or a pharmaceutically acceptable salt or ionized form thereof.
  • the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
  • a first assay is performed to determine a mean in vitro expression of the wild type K- ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about 1 mM of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K-ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horse
  • the mean in vitro expression of the wild type K-ras protein is determined to be within 1% of the mean control in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean in vitro expression of the wild type K-ras protein.
  • the non-wild type K-ras protein is K-ras G12D In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non- wild type K-ras protein is K-ras G12C.
  • the compound is a DNA binding agent. In some embodiments, the compound comprises a gamma-peptide nucleic acid. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene.
  • the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism.
  • the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a DNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T).
  • the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence that arises from transcription of the non-wild type KRAS gene over a mRNA sequence that arises from transcription of the wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non- wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the compound reduces transcription of the non-wild type KRAS gene.
  • the compound reduces translation of the mRNA sequence transcribed from the non- wild type KRAS gene.
  • the condition is a human cancer.
  • the human cancer is pancreatic ductal adenocarcinoma.
  • the human cancer is lung adenocarcinoma.
  • the human cancer is multiple myeloma.
  • the human cancer associated with the non-wild type KRAS gene is pancreatic cancer.
  • the human cancer associated with the non-wild type KRAS gene is HPAFII.
  • the human cancer associated with the non-wild type KRAS gene is CAPAN-II.
  • the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein.
  • the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
  • the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
  • a first assay is performed to determine a mean in vitro expression of the wild type K- ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about ImM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about ImM of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K- ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish
  • the mean in vitro expression of the wild type K-ras protein is determined to be within 5% of the mean control in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean control in vitro expression of the no- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean control in vitro expression of the nonwild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 65% lesser than to about 95% lesser than the mean control in vitro expression of the non-wild type K-ras protein. [00251] In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non- wild type K-ras protein is determined to be about 65% lesser than to about 95% lesser than the mean in vitro expression of the wild type K-ras protein.
  • the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non- wild type K-ras protein is K-ras G12C.
  • the compound is a nucleic acid binding agent. In some embodiments, the compound is a DNA binding agent. In some embodiments, the compound is a RNA binding agent. In some embodiments, the compound is a mRNA binding agent. In some embodiments, the compound comprises a gamma-peptide nucleic acid. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence that arises from transcription of the non-wild type KRAS gene.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence transcribed from the non- wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non- wild type KRAS gene , wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism.
  • the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a DNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a mRNA sequence transcribed from the non-wild type KRAS gene.
  • the compound reduces expression of the non-wild type K- ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene.
  • the compound preferentially binds to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound preferentially binds to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence that arises from transcription of the non- wild type KRAS gene over a mRNA sequence that arises from transcription of the wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K- ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the compound reduces transcription of the non- wild type KRAS gene.
  • the compound reduces translation of a mRNA sequence transcribed from the non-wild type KRAS gene.
  • the condition is a human cancer.
  • the human cancer is pancreatic ductal adenocarcinoma.
  • the human cancer is lung adenocarcinoma.
  • the human cancer is multiple myeloma.
  • the human cancer associated with the non-wild type KRAS gene is pancreatic cancer.
  • the human cancer associated with the non-wild type KRAS gene is HPAFII.
  • the human cancer associated with the non-wild type KRAS gene is CAPAN-II.
  • the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
  • the present disclosure provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm 3 to about 120 mm 3 , and a mean tumor volume size in the test group is observed to be from about 80 mm 3 to about 120 mm 3 ; on day 5 of the study, a mean tumor volume size in the control group is determined to be from about
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm 3 to about 120 mm 3 , and a mean tumor volume size in the test group is observed to be from about 80 mm 3 to about 120 mm 3 ; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm 3 to about 120 mm 3 , and a mean tumor volume size in the test group is observed to be from about 80 mm 3 to about 120 mm 3 ; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm 3 to about 10 mm 3 ; on day 5 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm 3 to about 10 mm 3 ; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm 3 to about 10 mm 3 ; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 90 mm 3 to about 110 mm 3 , and a mean tumor volume size in the test group is observed to be from about 90 mm 3 to about 110 mm 3 ; on day 4 of the study, a mean tumor volume size in the control group is determined to be from about 100
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 90 mm 3 to about 110 mm 3 , and a mean tumor volume size in the test group is observed to be from about 90 mm 3 to about 110 mm 3 ; on day 25 of the study, a mean tumor volume size in the control group is determined to be from about 310
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 90 mm 3 to about 110 mm 3 , and a mean tumor volume size in the test group is observed to be from about 90 mm 3 to about 110 mm 3 ; and on day 50 of the study, a mean tumor volume size in the control group is determined to be from about
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm 3 to about 10 mm 3 ; on day 4 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm 3 to about 10 mm 3 ; on day 25 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from
  • a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm 3 to about 10 mm 3 ; and on day 50 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse
  • a method of treating a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the
  • a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the
  • the compound is a DNA binding agent.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the KRAS gene of the subject, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the KRAS gene of the subject.
  • the peptide nucleic acid sequence is complementary to the non- wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene.
  • the peptide nucleic acid sequence is complementary to the non- wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism.
  • the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the gene of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a DNA sequence in the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to the mRNA sequence of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject. In some embodiments, the compound reduces expression of the non- wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject, wherein the mRNA sequence of the subject transcribed from non- wild type KRAS gene of the subject comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T).
  • the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound preferentially binds to the mRNA sequence transcribed from the non- wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non- wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the gene of the subject.
  • the compound reduces expression of the mutant protein by preferentially binding to the non-wild type gene over the wild-type gene. In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence transcribed from the non-wild type gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the compound reduces transcription of the non-wild type KRAS gene in the subject. In some embodiments, the compound reduces translation of the mRNA sequence transcribed from the non-wild type gene in the subject.
  • the condition is cancer.
  • the condition is cancer associated with a mutation in a KRAS gene
  • the condition is pancreatic ductal adenocarcinoma.
  • the condition is lung adenocarcinoma.
  • the condition is multiple myeloma.
  • the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma. In some embodiments, the human cancer associated with the non- wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II.
  • the therapeutically-effective amount is 0.01 mg/kg. In some embodiments, the therapeutically-effective amount is 0.05 mg/kg. In some embodiments, the therapeutically-effective amount is 0.1 mg/kg. In some embodiments, the therapeutically-effective amount is 0.2 mg/kg. In some embodiments, the therapeutically-effective amount is 0.3 mg/kg. In some embodiments, the therapeutically-effective amount is 0.4 mg/kg. In some embodiments, the therapeutically-effective amount is 0.5 mg/kg.
  • the administering is oral. In some embodiments, the administering is intravenous.
  • the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
  • the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A).
  • the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non- wild type K-ras protein is K-ras G12C.
  • the compound has the formula: whereineachBisindependentlythenucleobaseofthepluralityofnucleobase-bearingsidechains,whereinthepeptidenucleicacidsequencehasanucleobasesequencethatis:guanine,cytosine,cytosine,thymine,adenine,cytosine,guanine,cytosine,cytosine,adenine,thymine,cytosine,adenine,guanine,cytosine,thymine,cytosine,cytosine,cytosine,adenine,adenine,orapharmaceuticallyacceptablesaltorionizedformthereof[00347]Insomeembodiments,thecompoundhastheformula: whereineachofB 1 andB 2 isindependentlythenucleobaseofthepluralityofnucleobase-bearingsidechains,whereinthepeptidenucleicacidsequencehasanucleobasesequencethat
  • thepresentdisclosure providesamethodoftreatingaconditionassociatedwithnon-wildtypeKRAS,themethodcomprisingadministeringtoasubjectinneedthereofatherapeutically-effectiveamountofacompound,whereinthecompoundcomprisesapeptidenucleicacidsequence,whereinthepeptidenucleicacidsequencebindstoanucleicacidsequenceassociatedwithanon-wildtypeKRASgene,whereinif,inastudy: a) i) atestSCIDmousethatis5-9weeksoldisinoculatedwithaboutonemillionHPAF- IIcellsbysubcutaneousinjection,andatumorhavingavolumeofabout100mm 3 formsinthetestSCIDmouse; ii) afterthetumorforms,thetestSCIDmouseisdosedintratumorallyonceperweekfor threeconsecutiveweekswiththecompoundinavehicleatoneof0.3 ⁇ M,
  • the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be at most about 55% of the amount of phospho- MEK in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be about 40% to about 60% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be about 40% to about 50% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
  • the peptide nucleic acid sequence binds to a mRNA sequence transcribed from the non- wild type KRAS gene.
  • the condition is cancer. In some embodiments, the condition is cancer associated with a mutation in a KRAS gene. In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma.
  • the present disclosure provides a method of treating a condition associated with non-wild type KRAS, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid sequence associated with a non-wild type KRAS gene, wherein if, in a study: a) i) a test SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF- II cells by subcutaneous injection, and a tumor having a volume of about 100 mm 3 forms in the test SCID mouse; ii) after the tumor forms, the test SCID mouse is dosed intratumorally once per week for three consecutive weeks with the compound in a vehicle at one of 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, and 30 ⁇ M; iii) after the three consecutive weeks, the test
  • the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 40% of the amount of phospho- CREB in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 30% of the amount of phospho- CREB in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be from about 10% to about 30% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
  • the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be from about 15% to about 25% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
  • the peptide nucleic acid sequence binds to a mRNA sequence transcribed from the non- wild type KRAS gene.
  • the condition is cancer. In some embodiments, the condition is cancer associated with a mutation in a KRAS gene. In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma.
  • the compound has the formula: wherein each B is independently a nucleobase, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, thymine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, adenine, adenine, or a pharmaceutically acceptable salt, ionized form, or tautomer thereof.
  • the compound has the formula: wherein each of B 1 and B 2 is independently a nucleobase, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: thymine, guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, adenine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, or a pharmaceutically acceptable salt, ionized form, or tautomer thereof.
  • a compound provided herein or a composition comprising a compound provided herein can be administered to a subject in various forms and by various suitable routes of administration.
  • a compound provided herein or a composition comprising a compound provided herein can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant.
  • a compound provided herein or a composition comprising a compound provided herein can be administered in a systemic manner.
  • a compound provided herein or a composition comprising a compound provided herein is administered parenterally.
  • Parenteral administration can be, for example, by bolus injection or by gradual infusion or perfusion over time. Administration can also be by surgical deposition of a bolus or positioning of a medical device.
  • a compound provided herein or a composition comprising a compound provided herein is administered orally.
  • a compound provided herein or a composition comprising a compound provided herein is administered by an intravenous, intratumoral, subcutaneous, intramuscular, intracerebral, intracerebroventricular, intra-articular, intraperitoneal, intracranial, intrathecal, intranasal, buccal, sublingual, oral, or rectal administration route.
  • a compound provided herein or a composition comprising a compound provided herein is administered by intravenous administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by subcutaneous administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by intramuscular administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by intracerebroventricular administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by oral administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by intrathecal administration.
  • Any aforementioned route of administration can be combined with another route of administration.
  • a compound provided herein can be delivered by a first route of administration, and one or more subsequent maintenance doses of the compound can be delivered by the same or a different route of administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by intramuscular administration, and one or more subsequent maintenance doses of the compound or the composition comprising the compound are delivered by subcutaneous administration or intravenous administration.
  • Non-limiting examples of suitable modes and routes of administration include oral, topical, parenteral, intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, intramuscular infusion, intradermal injection, intradermal infusion, intraperitoneal injection, intraperitoneal infusion, intracerebral injection, intracerebral infusion, subarachnoid injection, subarachnoid infusion, intraocular injection, intraspinal injection, intrastemal injection, ophthalmic administration, endothelial administration, local administration, intranasal administration, intrapulmonary administration, rectal administration, intraarterial administration, intrathecal administration, inhalation, intralesional administration, intradermal administration, transdermal administration (e.g., via emulsion/liposome-mediated methods of delivery with the compound optionally packaged into liposomes), epidural administration, absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mu
  • a compound provided herein or a composition comprising a compound provided herein can be administered via a non-invasive method.
  • non-invasive modes of administering can include using a needleless injection device, and topical administration, e.g., eye drops. Multiple administration routes can be employed for efficient delivery.
  • the compositions can be in the form of solid, semi solid or liquid dosage forms, such as, e g., tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, e.g., in unit dosage form suitable for single administration of a precise dosage.
  • the composition can be formulated into any suitable dosage form for administration, e.g., aqueous dispersions, liquids, gels, syrups, elixirs, slurries, and suspensions, for administration to a subject or a patient.
  • Solid compositions include, e.g., powders, tablets, dispersible granules, capsules, and cachets.
  • Liquid compositions include, e.g., solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, e.g., gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions.
  • compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • the composition is formulated into solutions (e.g., for IV administration).
  • the pharmaceutical composition is formulated as an infusion.
  • the pharmaceutical composition is formulated as an injection.
  • a compound provided herein or a composition comprising a compound provided herein can be administered in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • a rapid release form can provide an immediate release.
  • An extended release formulation can provide a controlled release or a sustained delayed release.
  • a composition comprising a compound provided herein can be, e.g., an immediate release form or a controlled release formulation.
  • An immediate release formulation can be formulated to allow the compounds to act rapidly.
  • Non-limiting examples of immediate release formulations include readily dissolvable formulations.
  • a controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements, or has been formulated to effect release of an active agent at a programmed rate.
  • Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix -based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
  • a controlled release formulation is a delayed release form.
  • a delayed release form can be formulated to delay a compound’s action for an extended period of time.
  • a delayed release form can be formulated to delay the release of an effective dose of one or more compounds, e.g., for about 4, about 8, about 12, about 16, or about 24 hours.
  • a controlled release formulation can be a sustained release form.
  • a sustained release form can be formulated to sustain, e.g., the compound’s action over an extended period of time.
  • a sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.
  • a pharmaceutical composition disclosed herein can be targeted to any suitable tissue or cell type. Modes, routes, and compositions provided herein can be suitable to target a compound provided herein to a particular tissue, or a subset of tissues.
  • tissues that can be targeted include kidney (e.g., kidney cortex), joints, cartilage, liver, salivary glands, bone (e.g., bone surface), skin, lung, muscle, pancreas, hair follicles, large intestine mucosa, aortic wall, small intestine mucosa, adrenal gland, stomach mucosa, spleen, bone marrow, lymph nodes, thymus, brain, cerebellum, olfactory bulb, thalamus, caudate putamen, cerebral cortex, substantia nigra, lateral ventricle, choroid plexus, and combinations thereof.
  • Compounds can be introduced into cells by, e.g., transfection, electroporation, fusion, liposomes, colloidal polymeric particles, and viral and non-viral vectors.
  • Compounds provided herein can also be delivered using, e.g., methods involving liposome-mediated uptake, lipid conjugates, polylysine-mediated uptake, nanoparticle-mediated uptake, and receptor-mediated endocytosis, as well as additional non-endocytic modes of delivery, such as microinjection, permeabilization (e.g., streptolysin-O permeabilization, anionic peptide permeabilization), electroporation, and various non-invasive non-endocytic methods of delivery.
  • permeabilization e.g., streptolysin-O permeabilization, anionic peptide permeabilization
  • electroporation e.g., electroporation, and various non-invasive non-endocytic methods of delivery.
  • the method of delivery can depend at least on the cells to be treated and the location of the cells. For instance, localization can be achieved by liposomes with specific markers on the surface to direct the liposome, direct injection into tissue containing target cells, specific receptor mediated uptake, or viral vectors.
  • a compound disclosed herein is delivered via an implantable device, e.g., synthetic implant design.
  • Compounds provided herein can be administered in any physiologically and/or pharmaceutically acceptable vehicle or carrier.
  • pharmaceutically acceptable carriers include saline, phosphate buffered saline (PBS), water, aqueous ethanol, emulsions, such as oil/water emulsions or triglyceride emulsions, tablets, and capsules.
  • PBS phosphate buffered saline
  • emulsions such as oil/water emulsions or triglyceride emulsions, tablets, and capsules.
  • suitable physiologically acceptable carrier can vary depending upon the chosen mode of administration.
  • a pharmaceutically acceptable carrier can include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • prodrugs of a compound provided herein can be covalently bonded carriers that release a compound in vivo when administered to a subject.
  • Prodrugs can be prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, to yield the biologically active compound.
  • Non-limiting examples of prodrugs include acetate, formate, and benzoate derivatives of alcohol and amine functional groups of compounds provided herein.
  • esters can be used, such as methyl esters and ethyl esters.
  • liposomes can be used to facilitate uptake of a compound provided herein into cells.
  • Hydrogels can also be used as vehicles for compound administration.
  • a compound provided herein can be administered in microspheres or microparticles.
  • the use of gas-filled microbubbles complexed with a compound provided herein can enhance delivery to target tissues.
  • Sustained release compositions can also be used, including, e.g., semipermeable polymeric matrices in the form of shaped articles such as films or microcapsules.
  • a compound provided herein is administered to a mammalian subject, e.g., human or domestic animal that is exhibiting the symptoms of a polynucleotide repeat expansion disorder.
  • Compounds provided herein can selectively reduce expression of a mutant protein in the subject.
  • the subject is a human subject, e.g., a patient diagnosed as having a polynucleotide repeat disease.
  • a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered orally.
  • a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered intravenously.
  • the subject is a vertebrate. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a subject is a non-human subject. In some embodiments, a subject is a veterinary subject.
  • the patient is a vertebrate. In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the patient is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a patient is a non-human patient. In some embodiments, a patient is a veterinary patient.
  • a patient and a subject are the same species. In some embodiments, a subject and a patient are human.
  • a patient and a subject are different species.
  • a subject is human and a patient is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig.
  • a patient is human and a subject is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig.
  • a non-human vertebrate for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig.
  • An effective in vivo treatment regimen using the compounds provided herein can vary according to the duration, dose, frequency, and route of administration, as well as the condition of the subject under treatment (i.e., prophylactic administration versus administration in response to localized or systemic infection). Accordingly, such in vivo therapy can require monitoring by tests appropriate to the particular type of disorder under treatment, and corresponding adjustments in the dose or treatment regimen, in order to achieve an optimal therapeutic outcome.
  • the efficacy of an in vivo administered compound provided herein can be determined from biological samples (e.g., tissue, blood, urine) taken from a subject prior to, during, and subsequent to administration of the compound.
  • Assays of such samples can include (1) monitoring the presence or absence of heteroduplex formation with target and non-target sequences, e.g., by an electrophoretic gel mobility assay; and (2) monitoring the amount of a mutant mRNA or protein in relation to a reference wild-type mRNA or protein as determined by standard techniques such as RT-PCR, Northern blotting, ELISA, or Western blotting.
  • the compound provided herein is actively taken up by mammalian cells.
  • the compound provided herein can be conjugated to a transport moiety (e.g., transport peptide) as described herein to facilitate such uptake.
  • Compounds provided herein can be administered to subjects to treat (prophylactically or therapeutically) disorders associated with aberrant expression of a mRNA or protein produced from a mutant polynucleotide repeat containing allele.
  • pharmacogenomics i.e., the study of the relationship between an individual's genotype and the individual's response to a foreign compound or drug
  • Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug.
  • a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a therapeutic agent as well as tailoring the dosage and/or therapeutic regimen of treatment with the therapeutic agent.
  • the present disclosure provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the condition is associated with a non-wild type gene in the subject, wherein the non- wild type gene differs from a corresponding wild type gene in a single nucleotide polymorphism, wherein the single nucleotide polymorphism in the subject encodes for expression of a mutant protein that contributes to the condition, wherein the compound reduces expression of the mutant protein in the subject.
  • the compound is a nucleic acid binding agent. In some embodiments, the compound is a DNA binding agent. In some embodiments, the compound is a RNA binding agent. In some embodiments, the compound is a mRNA binding agent. In some embodiments, the compound comprises a peptide nucleic acid sequence. In some embodiments, the compound comprises a gamma-peptide nucleic acid sequence.
  • the compound comprises a plurality of nucleobase-bearing side chains. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with the non-wild type gene. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence that arises from transcription of the non-wild type gene.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with the non-wild type gene, wherein one nucleobase binds to the single nucleotide polymorphism.
  • the compound comprises a plurality of nucleobase- bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence that arises from transcription of the non-wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that is complementary to the non-wild type gene. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that is complementary to a mRNA sequence that arises from transcription of the non-wild type gene.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that is complementary to the non-wild type gene, wherein one nucleobase binds to the single nucleotide polymorphism.
  • the compound comprises a plurality of nucleobase- bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that is complementary to a mRNA sequence that arises from transcription of the non-wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject, and wherein one of the nucleobases from the sequence that is complementary to the mRNA sequence that arises from transcription of the non-wild type gene binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject.
  • the compound reduces expression of the mutant protein by binding to a nucleic acid of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a DNA sequence in the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a RNA sequence of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a mRNA sequence of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to the non-wild type gene of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a mRNA sequence of the subject that arises from transcription of the non-wild type gene of the subject.
  • the compound reduces expression of the mutant protein by binding to the single nucleotide polymorphism of the non-wild type gene of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a mRNA sequence of the subject that arises from transcription of the non-wild type gene of the subject, wherein the mRNA sequence of the subject that arises from transcription of the non-wild type gene of the subject comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subj ect.
  • the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T).
  • the compound preferentially binds to the non-wild type gene over the wild type gene. In some embodiments, the compound preferentially binds to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene. In some embodiments, the compound preferentially binds to the non-wild type gene over the wild-type gene, and wherein the compound binds the non-wild-type gene at the single nucleotide polymorphism.
  • the compound preferentially binds to a mRNA sequence that arises from transcription of the non- wild type gene over a mRNA sequence that arises from transcription of the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject.
  • the compound reduces expression of the mutant protein by preferentially binding to the non-wild type gene over the wild-type gene.
  • the compound reduces expression of the mutant protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene. In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to the non-wild type gene over the wild-type gene, and wherein the compound binds the non-wild-type gene at the single nucleotide polymorphism.
  • the compound reduces expression of the mutant protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject.
  • the compound reduces transcription of the non-wild type gene in the subject. In some embodiments, the compound reduces translation of the non-wild type gene in the subject.
  • the condition is cancer.
  • the condition is a human cancer.
  • the condition is cancer associated with a mutation in a KRAS gene.
  • the condition is pancreatic ductal adenocarcinoma.
  • the condition is lung adenocarcinoma.
  • the condition is multiple myeloma.
  • the human cancer is pancreatic ductal adenocarcinoma.
  • the human cancer is lung adenocarcinoma.
  • the human cancer is multiple myeloma.
  • the condition is a human cancer associated with a non-wild type KRAS gene that is HPAFII. In some embodiments, the condition is a human cancer associated with a non-wild type KRAS gene that is CAPAN-II. In some embodiments, the condition is the human cancer associated with a non- wild type KRAS gene is pancreatic cancer. In some embodiments, the human cancer associated with a non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with a non-wild type KRAS gene is CAPAN-II.
  • the therapeutically-effective amount is about 0.01 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.05 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.1 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.2 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.3 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.4 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.5 mg/kg.
  • the administering is oral. In some embodiments, the administering is intravenous. In some embodiments, the administering is subcutaneous.
  • the wild type gene is KRAS. In some embodiments, the non- wild type gene is mutant KRAS. In some embodiments, the wild type gene is KRAS, the non- wild type gene is mutant KRAS, and the single nucleotide polymorphism results in a G12D mutation in the mutant protein. In some embodiments, the wild type gene is KRAS, the non-wild type gene is mutant KRAS, and the single nucleotide polymorphism results in a G12V mutation in the mutant protein. In some embodiments, the wild type gene is KRAS, the non-wild type gene is mutant KRAS, and the single nucleotide polymorphism results in a G12C mutation in the mutant protein. In some embodiments, the mutant protein is K-ras G12D. In some embodiments, the mutant protein is K-ras G12V. In some embodiments, the mutant protein is K- ras G12C.
  • the present disclosure provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
  • a first assay is performed to determine a mean in vitro expression of the wild type K- ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about 1 mM of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K-ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horseradish
  • the mean in vitro expression of the wild type K-ras protein is determined to be within 1% of the mean control in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean in vitro expression of the wild type K-ras protein. [00407] In some embodiments, the non-wild type K-ras protein is K-ras G12D.
  • the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non- wild type K-ras protein is K-ras G12C.
  • the compound is a DNA binding agent. In some embodiments, the compound comprises a gamma-peptide nucleic acid. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene.
  • the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism.
  • the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non- wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a DNA sequence in the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a mRNA sequence of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene of the subject, wherein the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T).
  • the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non- wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene.
  • the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the nonwild-type KRAS gene at the single nucleotide polymorphism. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type KRAS gene over a mRNA sequence that arises from transcription of the wild type KRAS gene.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the nonwild-type KRAS gene at the single nucleotide polymorphism.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject.
  • the compound reduces transcription of the non-wild type KRAS gene in the subject.
  • the compound reduces translation of the mRNA sequence transcribed from the non-wild type KRAS gene in the subject.
  • the condition is cancer. In some embodiments, the condition is a human cancer. In some embodiments, the condition is cancer associated with a mutation in the non-wild type KRAS gene. In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma. In some embodiments, the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma.
  • the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II. In some embodiments, the human cancer associated with the non-wild type KRAS gene is pancreatic cancer. In some embodiments, the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non- wild type KRAS gene is CAPAN-II. In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein.
  • the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non- wild type K-ras protein. In some embodiments, the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non-wild type K-ras protein is K-ras G12C.
  • the therapeutically-effective amount is about 0.01 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.05 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.1 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.2 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.3 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.4 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.5 mg/kg.
  • the administering is oral. In some embodiments, the administering is intravenous. In some embodiments, the administering is subcutaneous.
  • the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
  • the present disclosure provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
  • a first assay is performed to determine a mean in vitro expression of the wild type K- ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about 1 mM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about 1 mM of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K- ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated
  • the mean in vitro expression of the wild type K-ras protein is determined to be within 5% of the mean control in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean control in vitro expression of the nonwild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 65% lesser than to about 95% lesser than the mean control in vitro expression of the non-wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean in vitro expression of the wild type K-ras protein.
  • the mean in vitro expression of the nonwild type K-ras protein is determined to be about 65% lesser than to about 95% lesser than the mean in vitro expression of the wild type K-ras protein.
  • the non-wild type K-ras protein is K-ras G12D.
  • the non-wild type K-ras protein is K- ras G12V.
  • the non-wild type K-ras protein is K-ras G12C.
  • the compound is a nucleic acid binding agent. In some embodiments, the compound is a DNA binding agent. In some embodiments, the compound is a RNA binding agent. In some embodiments, the compound is a mRNA binding agent. In some embodiments, the compound comprises a gamma-peptide nucleic acid. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence that arises from transcription of the non-wild type KRAS gene.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
  • the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence transcribed from the non- wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non- wild type KRAS gene of the subject, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism.
  • the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a DNA sequence in the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence of the subj ect. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a mRNA sequence of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a mRNA sequence of the subject transcribed from the non- wild type KRAS gene of the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the compound reduces expression of the non-wild type K-ras protein by binding to a mRNA sequence transcribed from the non-wild type KRAS gene of the subject, wherein the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene.
  • the compound preferentially binds to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound preferentially binds to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the compound reduces expression of the non- wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild- type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type KRAS gene over a mRNA sequence that arises from transcription of the wild type KRAS gene.
  • the compound reduces expression of the non-wild type K- ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
  • the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence transcribed from the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
  • the compound reduces transcription of the non-wild type KRAS gene in the subject. In some embodiments, the compound reduces translation of a mRNA sequence transcribed from the non-wild type KRAS gene in the subject.
  • the condition is cancer. In some embodiments, the condition is a human cancer. In some embodiments, the condition is cancer associated with a mutation in the non-wild type KRAS gene. In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma. In some embodiments, the human cancer is pancreatic ductal adenocarcinoma.
  • the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma. In some embodiments, the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II. In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein.
  • the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
  • the non-wild type K-ras protein is K-ras G12D.
  • the non-wild type K-ras protein is K-ras G12V.
  • the non-wild type K-ras protein is K-ras G12C.
  • the therapeutically-effective amount is about 0.01 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.05 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.1 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.2 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.3 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.4 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.5 mg/kg. In some embodiments, the administering is oral. In some embodiments, the administering is intravenous. In some embodiments, the administering is subcutaneous.
  • the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
  • the subject is a vertebrate. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a subject is a non-human subject. In some embodiments, a subject is a veterinary subject.
  • compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the dosage e.g., therapeutically-effective amount
  • for a compound described herein can be in any amount necessary.
  • a compound described herein can be present in a composition or a unit dose in a range of from about 1 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 25 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg
  • a compound described herein can be present in a composition or a unit dose in a range of from about 1 ⁇ g to about 2000 ⁇ g; from about 5 ⁇ g to about 1000 ⁇ g, from about 10 ⁇ g to about 25 ⁇ g, from about 50 ⁇ g to about 250 ⁇ g, from about 100 ⁇ g to about 200 ⁇ g, from about 1 ⁇ g to about 50 ⁇ g, from about 50 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 150 ⁇ g, from about 150 ⁇ g to about 200 ⁇ g, from about 200 ⁇ g to about 250 ⁇ g, from about 250 ⁇ g to about 300 ⁇ g, from about 300 ⁇ g to about 350 ⁇ g, from about 350 ⁇ g to about 400 ⁇ g, from about 400 ⁇ g to about 450 ⁇ g, from about 450 ⁇ g to about 500 ⁇ g, from about 500 ⁇ g to about 550 ⁇ g, from about 550 ⁇ g to about 600 ⁇ g, from about 600
  • a compound described herein can be present in a composition or a unit dose in an amount of about 0.001 mg, about 0.002 mg, about 0.003 mg, about 0.004 mg, about 0.005 mg, about 0.006 mg, about 0.007 mg, about 0.008 mg, about 0.009 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about
  • a composition is present in a composition or a unit dose in an amount that is at least about 0.001 mg, at least about 0.002 mg, at least about 0.003 mg, at least about 0.004 mg, at least about 0.005 mg, at least about 0.006 mg, at least about 0.007 mg, at least about 0.008 mg, at least about 0.009 mg, at least about 0.01 mg, at least about 0.02 mg, at least about 0.03 mg, at least about 0.04 mg, at least about 0.05 mg, at least about 0.06 mg, at least about 0.07 mg, at least about 0.08 mg, at least about 0.09 mg, at least about 0.1 mg, at least about 0.2 mg, at least about 0.3 mg, at least about 0.4 mg, at least about 0.5 mg, at least about 0.6 mg, at least about 0.7 mg, at least about 0.8 mg, at least about 0.9 mg, at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5
  • a composition is present in a composition or a unit dose in an amount that is at most about 0.001 mg, at most about 0.002 mg, at most about 0.003 mg, at most about 0.004 mg, at most about 0.005 mg, at most about 0.006 mg, at most about 0.007 mg, at most about 0.008 mg, at most about 0.009 mg, at most about 0.01 mg, at most about 0.02 mg, at most about 0.03 mg, at most about 0.04 mg, at most about 0.05 mg, at most about 0.06 mg, at most about 0.07 mg, at most about 0.08 mg, at most about 0.09 mg, at most about 0.1 mg, at most about 0.2 mg, at most about 0.3 mg, at most about 0.4 mg, at most about 0.5 mg, at most about 0.6 mg, at most about 0.7 mg, at most about 0.8 mg, at most about 0.9 mg, at most about 1 mg, at most about 2 mg, at most about 3 mg, at most about 4 mg, at most about 5
  • a dose (e.g., a unit dose) is about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.007 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg
  • a dose is at least about 0.001 mg/kg, at least about 0.002 mg/kg, at least about 0.003 mg/kg, at least about 0.004 mg/kg, at least about 0.005 mg/kg, at least about 0.006 mg/kg, at least about 0.007 mg/kg, at least about 0.008 mg/kg, at least about 0.009 mg/kg, at least about 0.01 mg/kg, at least about 0.02 mg/kg, at least about 0.03 mg/kg, at least about 0.04 mg/kg, at least about 0.05 mg/kg, at least about 0.06 mg/kg, at least about 0.07 mg/kg, at least about 0.08 mg/kg, at least about 0.09 mg/kg, at least about 0.1 mg/kg, at least about 0.2 mg/kg, at least about 0.3 mg/kg, at least about 0.4 mg/kg, at least about 0.5 mg/kg, at least about 0.6 mg/kg, at least about 0.7
  • a dose (e.g., a unit dose) is at most about 0.001 mg/kg, at most about 0.002 mg/kg, at most about 0.003 mg/kg, at most about 0.004 mg/kg, at most about 0.005 mg/kg, at most about 0.006 mg/kg, at most about 0.007 mg/kg, at most about 0.008 mg/kg, at most about 0.009 mg/kg, at most about 0.01 mg/kg, at most about 0.02 mg/kg, at most about 0.03 mg/kg, at most about 0.04 mg/kg, at most about 0.05 mg/kg, at most about 0.06 mg/kg, at most about 0.07 mg/kg, at most about 0.08 mg/kg, at most about 0.09 mg/kg, at most about 0.1 mg/kg, at most about 0.2 mg/kg, at most about 0.3 mg/kg, at most about 0.4 mg/kg, at most about 0.5 mg/kg, at most about 0.6 mg/kg, at most about 0.7
  • a dose is from about 0.1 mg/kg to about 2000 mg/kg, from about 1 mg/kg to about 2000 mg/kg, from about 5 mg/kg to about 1000 mg/kg, from about 10 mg/kg to about 25 mg/kg, from about 50 mg/kg to about 250 mg/kg, from about 100 mg/kg to about 200 mg/kg, from about 1 mg/kg to about 50 mg/kg, from about 50 mg/kg to about 100 mg/kg, from about 100 mg/kg to about 150 mg/kg, from about 150 mg/kg to about 200 mg/kg, from about 200 mg/kg to about 250 mg/kg, from about 250 mg/kg to about 300 mg/kg, from about 300 mg/kg to about 350 mg/kg, from about 350 mg/kg to about 400 mg/kg, from about 400 mg/kg to about 450 mg/kg, from about 450 mg/kg to about 500 mg/kg, from about 500 mg/kg to about 550 mg/kg, from about 550 mg
  • compositions and formulations described herein can comprise, for example, a compound provided herein at any suitable concentration.
  • a formulation can comprise a composition provided herein at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg
  • a formulation provided herein comprises a compound provided herein at a concentration of at least about 0.001 mg/mL, at least about 0.002 mg/mL, at least about 0.003 mg/mL, at least about 0.004 mg/mL, at least about 0.005 mg/mL, at least about 0.006 mg/mL, at least about 0.007 mg/mL, at least about 0.008 mg/mL, at least about 0.009 mg/mL, at least about 0.01 mg/mL, at least about 0.02 mg/mL, at least about 0.03 mg/mL, at least about 0.04 mg/mL, at least about 0.05 mg/mL, at least about 0.06 mg/mL, at least about 0.07 mg/mL, at least about 0.08 mg/mL, at least about 0.09 mg/mL, at least about 0.1 mg/mL, at least about 0.2 mg/mL, at least about 0.3 mg/mL, at least about 0.4 mg/m
  • a formulation provided herein comprises a compound provided herein at a concentration of at most about 0.002 mg/mL, at most about 0.003 mg/mL, at most about 0.004 mg/mL, at most about 0.005 mg/mL, at most about 0.006 mg/mL, at most about 0.007 mg/mL, at most about 0.008 mg/mL, at most about 0.009 mg/mL, at most about 0.01 mg/mL, at most about 0.02 mg/mL, at most about 0.03 mg/mL, at most about 0.04 mg/mL, at most about 0.05 mg/mL, at most about 0.06 mg/mL, at most about 0.07 mg/mL, at most about 0.08 mg/mL, at most about 0.09 mg/mL, at most about 0.1 mg/mL, at most about 0.2 mg/mL, at most about 0.3 mg/mL, at most about 0.4 mg/mL, at most about 0.5 mg/mL
  • a formulation provided herein comprises a compound provided herein at a concentration of about 1 mg/mL to about 2000 mg/mL; from about 5 mg/mL to about 1000 mg/mL, from about 10 mg/mL to about 25 mg/mL, from about 50 mg/mL to about 250 mg/mL, from about 100 mg/mL to about 200 mg/mL, from about 1 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 100 mg/mL, from about 100 mg/mL to about 150 mg/mL, from about 150 mg/mL to about 200 mg/mL, from about 200 mg/mL to about 250 mg/mL, from about 250 mg/mL to about 300 mg/mL, from about 300 mg/mL to about 350 mg/mL, from about 350 mg/mL to about 400 mg/mL, from about 400 mg/mL to about 450 mg/mL, from about 450 mg/mL to about 500 mg/mL, from
  • a formulation of the disclosure delivers about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg AED of a compound of the disclosure.
  • a formulation of the disclosure delivers about 0.1 mg/kg AED of a compound of the disclosure.
  • a formulation of the disclosure delivers about 0.2 mg/kg AED of a compound of the disclosure.
  • a formulation of the disclosure delivers about 03 mg/kg AED of a compound of the disclosure.
  • An approximate dose can be predicted or determined on the basis of data existing in other species.
  • allometric scaling can be used to exchange a drug dose based on normalization of dose to body surface area. Allometric scaling considers the sizes of individual species based on body surface area, which is related to metabolic rate of an animal that is established through evolutionary adaptation of animals to their size.
  • a no observed adverse effect level (NOAEL) is first determined in an animal species, the NOAEL is converted to a human equivalent dose (HED), an appropriate animal species is selected, a safety factor is applied, and a pharmacologically active dose is determined.
  • NOAEL no observed adverse effect level
  • NOAEL the highest dose level that does not cause significant adverse effects, is a typical index for safety obtained from animal experiments to determine a safe starting dose. NOAEL values can be converted to HED on the basis of the body surface correction factor using appropriate scaling factors from animal species. TABLE 5 lists HED calculation guidelines based on body surface areas. HED is determined using the equation:
  • HED Animal NOAEL (mg/kg) x (Weight animal [kg]/Weight human [kg]) (1-067) [00441]
  • the HED is divided by a factor value of 10 to increase safety of the first human dose.
  • the safety factor is accountable for differences in physiological and biological processes between human and animal species.
  • the correction factor (K m ) is estimated by dividing the average body weight (kg) of a species to its body surface area (m 2 ).
  • the K m factor values of various animal species of TABLE 5 is used to estimate the HED as:
  • conversion between species based on mg/m 2 is not supported for drugs administered by topical, nasal, subcutaneous, or intramuscular routes, as well as proteins administered parenterally with molecular weight >100,000 Daltons.
  • TABLE 6 provides animal equivalent dose (AED) calculation guidelines based on body surface area.
  • the animal equivalent dose (AED) can also be calculated on the basis of body surface area by either dividing or multiplying the human dose (mg/kg) by the K m ratio provided in TABLE 6.
  • AED can be calculated using the equation:
  • AED (mg/kg) Human doses (mg/kg) x K m ratio TABLE 6
  • Dog 10 20 1.8 0.541
  • HED conversion (mg/kg) is also based on body surface area normalization. The conversion can be made by dividing the NOAEL in appropriate species by the conversion factor. TABLE 7 provides guidelines for maximum injection volume, by species, site location, and gauge size. Injection volume of parenteral formulation is calculated by the following equation:
  • Injection volume (mL) [Animal weight (kg) x Animal doses (mg/kg)] / Concentration (mg/kg)
  • a pharmaceutical composition of the disclosure can be used, for example, before, during, or after treatment of a subject with, for example, another pharmaceutical agent.
  • Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals.
  • a subject is a patient.
  • a pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration.
  • a pharmaceutical composition can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant.
  • Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • a rapid release form can provide an immediate release.
  • An extended release formulation can provide a controlled release or a sustained delayed release.
  • pharmaceutical compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject.
  • Non-limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hy droxy ethyl- 1- piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC).
  • Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremophor, DMSO, and potassium phosphate buffer.
  • compositions can be formulated for intravenous administration.
  • the pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments.
  • Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • the compounds of the disclosure can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject.
  • the compounds of the disclosure can be applied to an accessible body cavity.
  • the compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, and PEG.
  • rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas
  • conventional suppository bases such as cocoa butter or other glycerides
  • synthetic polymers such as polyvinylpyrrolidone, and PEG.
  • a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be melted.
  • therapeutically-effective amounts of the compounds described herein can be administered in pharmaceutical compositions to a subject having a disease or condition to be treated.
  • the subject is a mammal such as a human.
  • a therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulations can be modified depending upon the route of administration chosen.
  • Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.
  • compositions can include at least one pharmaceutically-acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically- acceptable salt form.
  • Pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets.
  • Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, for example, gels, suspensions and creams.
  • compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.
  • Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.
  • a composition of the disclosure can be, for example, an immediate release form or a controlled release formulation.
  • An immediate release formulation can be formulated to allow the compounds to act rapidly.
  • Non-limiting examples of immediate release formulations include readily dissolvable formulations.
  • a controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate.
  • Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
  • hydrogels e.g., of synthetic or natural origin
  • other gelling agents e.g., gel-forming dietary fibers
  • matrix-based formulations e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through
  • a controlled release formulation is a delayed release form.
  • a delayed release form can be formulated to delay a compound’s action for an extended period of time.
  • a delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.
  • a controlled release formulation can be a sustained release form.
  • a sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time.
  • a sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16 or about 24 hours.
  • Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.
  • Multiple therapeutic agents can be administered in any order or simultaneously.
  • a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent.
  • the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills.
  • the agents can be packed together or separately, in a single package or in a plurality of packages.
  • One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month.
  • Therapeutic agents described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a therapeutic agent can vary.
  • the compositions can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen a likelihood of the occurrence of the disease or condition.
  • the compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of the therapeutic agents can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
  • the initial administration can be via any route practical, such as by any route described herein using any formulation described herein.
  • a compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
  • the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15
  • compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
  • the unit dosage can be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged injectables, vials, or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative.
  • Formulations for injection can be presented in unit dosage form, for example, in ampoules, or in multi dose containers with a preservative.
  • compositions provided herein can be administered in conjunction with other therapies, for example, chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins.
  • the other agents can be administered prior to, after, or concomitantly with the pharmaceutical compositions.
  • the pharmaceutical compositions can be in the form of solid, semi solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in unit dosage form suitable for single administration of a precise dosage.
  • nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.
  • Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of the disclosure include anti-infectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics/antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.
  • anti-infectives i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics/antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.
  • Compounds can be delivered via liposomal technology. The use of liposomes as drug carriers can increase the therapeutic index of the compounds.
  • Liposomes are composed of natural phospholipids, and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine).
  • a liposome design can employ surface ligands for attaching to unhealthy tissue.
  • Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV).
  • LUV multilamellar vesicle
  • SUV small unilamellar vesicle
  • LUV large unilamellar vesicle
  • Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to reduce a likelihood of developing premature degradation and toxicity to non-target tissues.
  • Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, smallsized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally, liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells.
  • targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.
  • Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof.
  • Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti -adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.
  • compositions of the disclosure can be packaged as a kit.
  • a kit includes written instructions on the administration/use of the composition.
  • the written material can be, for example, a label.
  • the written material can suggest conditions methods of administration.
  • the instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.
  • the written material can be a label.
  • the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.
  • FDA U.S. Food and Drug Administration
  • EMA European Medicines Agency
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in a unit dosage form: a) a pharmaceutically-acceptable excipient; and b) an amount of a compound that is therapeutically-effective for treatment of a cancer associated with a KRAS mutation, the compound comprising a structure that binds to a sequence of nucleic acids encoding a KRAS gene, wherein the structure is:
  • N-Terminus is H, acyl, a group that together with the nitrogen atom to which A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H; each R alph a is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle;
  • C-Terminus is OH, OMe, or NH 2
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent
  • L1 is a linker group or absent
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • PEP1 is absent.
  • PEP1 is the peptide sequence.
  • the peptide sequence of PEP 1 is a nuclear localization sequence.
  • PEP1 is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1).
  • PEP1 is Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2).
  • PEP1 is -Ala-Lys-Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 77). In some embodiments, PEP1 is -Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 78). In some embodiments, PEP1 is -Arg-Arg-. In some embodiments, PEP1 is -Arg-Phe-Gln-Ile-Leu-Tyr-Arg- (SEQ ED NO: 86). In some embodiments, PEP2 is absent. In some embodiments, PEP2 is the peptide sequence.
  • the peptide sequence of PEP2 is a nuclear localization sequence.
  • PEP2 is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1).
  • PEP2 is Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2).
  • PEP2 is -Arg-Arg-.
  • PEP2 is -Arg-Phe-Gln-Ile-Leu-Tyr- Arg- (SEQ ID NO: 86).
  • SOLI is absent.
  • SOL1 is the water- solubilizing group.
  • the water-solubilizing group of SOL1 is a peptide sequence.
  • the water-solubilizing group of SOL1 is a group that contains multiple electrical charges at physiological pH.
  • the water-solubilizing group of SOLI is a group that contains multiple positive charges at physiological pH.
  • the water- solubilizing group of SOL1 is a polyethyleneglycol group.
  • the water- solubilizing group of SOL1 is -Arg-Arg-NH(CH 2 ) 2 C(0)-Arg-Arg-.
  • the sequence of nucleic acids encoding the KRAS gene is a mRNA sequence.
  • the sequence of nucleic acids encoding the KRAS gene is a DNA sequence.
  • the water-solubilizing group of SOLI is a group of formula:
  • R 1a is H, alkyl, or a nitrogen atom protecting group
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group
  • R 4a is H, alkyl, or a nitrogen atom protecting group
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), orN(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
  • the water-solubilizing group of SOL1 is a group of formula: wherein p is an integer that is 1-1,000. In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8.
  • p is an integer that is 7. [00482] In some embodiments, SOL2 is absent. In some embodiments, SOL2 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL2 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL2 is a polyethyleneglycol group.
  • the water- solubilizing group of SOL2 is -Arg-Arg-NH(CH 2 ) 2 C(0)-Arg-Arg-. [00483] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
  • R 1a is H, alkyl, or a nitrogen atom protecting group
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group;
  • R 4a is H, alkyl, or a nitrogen atom protecting group;
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), orN(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
  • the water-solubilizing group of SOL2 is a group of formula: wherein p is an integer that is 1-1,000. In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8. In some embodiments, p is an integer that is 7. [00485] In some embodiments, PNA1 is the peptide nucleic acid sequence. In some embodiments, PNA2 is the peptide nucleic acid sequence.
  • L1 is the linker group. In some embodiments, the linker group of L1 is cleavable. In some embodiments, the linker group of L1 is non-cleavable. In some embodiments, the linker group of L1 is a peptide sequence. In some embodiments, the linker group of L1 is a polyamine sequence. In some embodiments, the linker group of L1 is a polyamide sequence. In some embodiments, the linker group of LI is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L1 is a residue of an omega-amino caproic acid.
  • the linker group of L1 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L1 is a residue of oxalic acid. In some embodiments, the linker group of L1 is a residue of succinic acid. In some embodiments, the linker group of L1 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L1 is - NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(O)-.
  • the linker group of L1 is -NHCH(COOH)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(O)-.
  • the linker group of LI is -Arg-NH(CH 2 ) 5 C(O)-.
  • the linker group of L1 is - NH(CH 2 ) 5 C(O)-
  • the linker group of LI is -NH(CH 2 ) 2 C(O)-Arg- NH(CH 2 ) 5 C(O)NH(CH 2 ) 2 C(O)-.
  • the linker group of L1 is - NH(CH 2 ) 5 C(O)-Arg-NH(CH 2 ) 2 C(O)-Arg-NH(CH 2 ) 5 C(O)-Arg-NH(CH 2 ) 2 C(O).
  • L2 is the linker group. In some embodiments, the linker group of L2 is cleavable. In some embodiments, the linker group of L2 is non-cleavable. In some embodiments, the linker group of L2 is a peptide sequence. In some embodiments, the linker group of L2 is a polyamine sequence. In some embodiments, the linker group of L2 is a polyamide sequence. In some embodiments, the linker group of L2 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L2 is a residue of an omega-amino caproic acid.
  • the linker group of L2 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L2 is a residue of oxalic acid. In some embodiments, the linker group of L2 is a residue of succinic acid. In some embodiments, the linker group of L2 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L2 is - NHCH(COOH)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(O)-.
  • the linker group of L2 is -NHCH(COOO)C(CH 3 ) 2 S-SCH 2 CH(1SIH 2 )C(0)-. In some embodiments, the linker group of L2 is -Arg-NH(CH 2 ) 5 C(O)-. In some embodiments, the linker group of L2 is - NH(CH 2 ) 5 C(O)-. In some embodiments, the linker group of L2 is -NH(CH 2 ) 2 C(O)-Arg- NH(CH 2 ) 5 C(O)KH(CH 2 ) 2 C(O)-. In some embodiments, the linker group of L2 is - NH(CH2) 5 C(O)-Arg-NH(CH2) 5 C(O)-Arg-NH(CH2)2C(O).
  • L3 is the linker group. In some embodiments, the linker group of L3 is cleavable. In some embodiments, the linker group of L3 is non-cleavable. In some embodiments, the linker group of L3 is a peptide sequence. In some embodiments, the linker group of L3 is a polyamine sequence. In some embodiments, the linker group of L3 is a polyamide sequence. In some embodiments, the linker group of L3 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L3 is a residue of an omega-amino caproic acid.
  • the linker group of L3 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L3 is a residue of oxalic acid. In some embodiments, the linker group of L3 is a residue of succinic acid. In some embodiments, the linker group of L3 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L3 is - NHCH(COOH)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(O)-.
  • the linker group of L3 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(O)-. In some embodiments, the linker group of L3 is -Arg-NH(CH 2 ) 5 C(O)-. In some embodiments, the linker group of L3 is - NH(CH 2 ) 5 C(O)-. In some embodiments, the linker group of L3 is -NH(CH 2 ) 2 C(O)-Arg- NH(CH 2 ) 5 C(O)NH(CH 2 ) 2 C(O)-.
  • the linker group of L3 is - NH(CH 2 ) 5 C(O)-Arg-NH(CH 2 ) 2 C(O)-Arg-NH(CH 2 ) 5 C(O)-Arg-NH(CH 2 ) 2 C(O).
  • L4 is the linker group. In some embodiments, the linker group of L4 is cleavable. In some embodiments, the linker group of L4 is non-cleavable. In some embodiments, the linker group of L4 is a peptide sequence. In some embodiments, the linker group of L4 is a polyamine sequence. In some embodiments, the linker group of L4 is a polyamide sequence. In some embodiments, the linker group of L4 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L4 is a residue of an omega-amino caproic acid.
  • the linker group of L4 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L4 is a residue of oxalic acid. In some embodiments, the linker group of L4 is a residue of succinic acid. In some embodiments, the linker group of L4 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L4 is - NHCH(COOH)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(O)-.
  • the linker group of L4 is -NHCH(COOH)C(CH 3 ) 2 S-SCH 2 CH(1SIH 2 )C(O)-. In some embodiments, the linker group of L4 is -Arg-NH(CH2)5C(O)-. In some embodiments, the linker group of L4 is - NH(CH 2 ) 5 C(O)-. In some embodiments, the linker group of L4 is -NH(CH 2 ) 2 C(O)-Arg- NH(CH 2 ) 5 C(O)NH(CH 2 ) 2 C(O)-. In some embodiments, the linker group of L4 is - NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2) 5 C(O)-Arg-NH(CH2)2C(O).
  • L5 is the linker group. In some embodiments, the linker group of L5 is cleavable. In some embodiments, the linker group of L5 is non-cleavable. In some embodiments, the linker group of L5 is a peptide sequence. In some embodiments, the linker group of L5 is a polyamine sequence. In some embodiments, the linker group of L5 is a polyamide sequence. In some embodiments, the linker group of L5 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L5 is a residue of an omega-amino caproic acid.
  • the linker group of L5 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L5 is a residue of oxalic acid. In some embodiments, the linker group of L5 is a residue of succinic acid. In some embodiments, the linker group of L5 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L5 is - NHCH(COOH)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(O)-.
  • the linker group of L5 is -NHCH(COOH)C(CH3) 2 S-SCH 2 CH(NH 2 )C(O)-. In some embodiments, the linker group of L5 is -Arg-NH(CH 2 ) 5 C(O)-. In some embodiments, the linker group of L5 is - NH(CH 2 ) 5 C(O)-. In some embodiments, the linker group of L5 is -NH(CH 2 ) 2 C(O)-Arg- NH(CH 2 ) 5 C(O)NH(CH 2 ) 2 C(O)-.
  • the linker group of L5 is - NH(CH 2 ) 5 C(O)-Arg-NH(CH 2 ) 2 C(O)-Arg-NH(CH 2 ) 5 C(O)-Arg-NH(CH 2 ) 2 C(O).
  • L6 is the linker group. In some embodiments, the linker group of L 6 is cleavable. In some embodiments, the linker group of L6 is non-cleavable. In some embodiments, the linker group of L6 is a peptide sequence. In some embodiments, the linker group of L6 is a polyamine sequence. In some embodiments, the linker group of L6 is a polyamide sequence. In some embodiments, the linker group of L6 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L6 is a residue of an omega-amino caproic acid.
  • the linker group of L6 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L6 is a residue of oxalic acid. In some embodiments, the linker group of L6 is a residue of succinic acid. In some embodiments, the linker group of L6 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L6 is - NHCH(COOH)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(O)-.
  • the linker group of L6 is -NHCH(COOH)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(O)-. In some embodiments, the linker group of L6 is -Arg-NH(CH2)5C(O)-. In some embodiments, the linker group of L6 is - NH(CH 2 ) 5 C(O)-. In some embodiments, the linker group of L6 is -NH(CH 2 ) 2 C(O)-Arg- NH(CH 2 ) 5 C(O)NH(CH 2 ) 2 C(OO-. In some embodiments, the linker group of L6 is - NH(CH2)5C(0)-Arg-NH(CH2)2C(O)-Arg-NH(CH2) 5 C(O)-Arg-NH(CH2)2C(O).
  • the structure is:
  • N-Terminus wherein: the number of units with variables defined independently is at least 3;
  • N-Terminus is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H; each R alph a is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; and
  • C-Terminus is OH, OMe, NH 2 , or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the structure is: [00494] In some embodiments, the structure binds to a nucleic acid sequence encoding a KRAS gene by interactions between the heterocycles of the R 2 groups and nucleobases of the KRAS gene.
  • the KRAS gene is a non-wild type KRAS gene. In some embodiments, the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism
  • the single nucleotide polymorphism causes a mutation that is G12D. In some embodiments, the single nucleotide polymorphism causes a mutation that is G12V.
  • the single nucleotide polymorphism causes a mutation that is G12C.
  • the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
  • the number of units with variables defined independently is 3- 1,000. In some embodiments, the number of units with variables defined independently is 3-100. In some embodiments, the number of units with variables defined independently is 3-50. In some embodiments, the number of units with variables defined independently is 3, 4, 5, 6, 7, 8, embodiments, the number of units with variables defined independently is at least 11. In some embodiments, the number of units with variables defined independently is 11-1,000. In some embodiments, the number of units with variables defined independently is 11-100. In some embodiments, the number of units with variables defined independently is 11-50. In some embodiments, the number of units with variables defined independently is 11, 12, 13, 14, 15, 16,
  • each R 1 is independently alkyl that is unsubstituted. In some embodiments, each alkyl that is unsubstituted is independently methyl, ethyl, prop-1-yl, prop-2- yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent-1-yl. In some embodiments, each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-1-yl, or but-2-yl. In some embodiments, each R 1 is independently alkyl that is substituted.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N -methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1- hydroxyeth-1-yl, sulfhydrylmethyl, 2-thiomethyleth-1-yl, 4-aminobut-1-yl, 3-aminoprop-1-yl, 1- H -imidazol-ylmethyl, 1 -H -indol-3-ylmethyl, benzyl, 4-hydroxyphen-1-ylmethyl, 2- carboxylatoeth-1-yl, 3-carboxylatoprop-1-yl, 3 -guani dinoprop- 1-yl, 4-guanidinobut-1-yl, 2- carbamoyleth-1-yl, or 3-carbamoylprop-1-yl.
  • each R 1 is independently H, hydroxylmethyl, or 4-guanidinobut- 1yl. In some embodiments, at least one iteration of R 1 is hydroxylmethyl. In some embodiments, at least a third of the iterations of R 1 are hydroxylmethyl. In some embodiments, at least half the iterations ofR 1 are hydroxylmethyl. [00497] In some embodiments, each R alpha is independently alkyl that is unsubstituted. In some embodiments, each alkyl that is unsubstituted is independently methyl, ethyl, prop- 1-yl, prop-2- yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent-1-yl. In some embodiments, each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, or but-2-yl.
  • each R alpha is independently alkyl that is substituted.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, - NH 2 a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a l'-methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-1-yl, sulfhydrylmethyl, 2-thiomethyleth-1-yl, 4-aminobut-1-yl, 3- aminoprop-1-yl, 1 -H -imidazol-4-yl methyl, 1 -H -indol-3-ylmethyl, benzyl, 4-hydroxyphen-1- ylmethyl, 2-carboxylatoeth-1-yl, 3-carboxylatoprop-1-yl, 3-guani dinoprop- 1-yl, 4-guanidinobut- 1-yl, 2-carbamoyleth-1-yl, or 3-carbamoylprop-1-yl.
  • each R alpha is independently H, 3 -guani dinoprop- 1-yl, or 4- guanidinobut-l-yl. In some embodiments, at least one iteration of R alpha is 3 -guani dinoprop- 1-yl. In some embodiments, at least a third of the iterations of R alpha are 3 -guani dinoprop- 1-yl. In some embodiments, at least half the iterations of R alpha are 3 -guani dinoprop- 1-yl.
  • the first, third, sixth, ninth, eleventh, thirteenth, sixteenth, nineteenth, and twenty- second units, independently if present, are each 3-guanidinoprop-1-yl.
  • At least a third of the R 2 groups in the structure are methyl substituted with a heterocycle. In some embodiments, at least half of the R 2 groups in the structure are methyl substituted with a heterocycle.
  • the heterocycles of the R 2 groups are nucleobases or analogues of nucleobases. In some embodiments, at least one of the heterocycles of the R 2 groups is a divalent nucleobase. In some embodiments, the heterocycles of the R 2 groups are divalent nucleobases. In some embodiments, the heterocycles of the R 2 groups are each independently:
  • each R 2 is independently: methyl, OMe,
  • the N-terminus is H. In some embodiments, the N-terminus is acyl. In some embodiments, the N-terminus is the biological agent. In some embodiments, the biological agent is a vitamin E group. In some embodiments, the biological agent is an O-bound tocopherol group. In some embodiments, C-Terminus is NH 2 . In some embodiments, C- Terminus is -Pro-Lys-Lys-Lys-Arg-Lys-Val-NH 2 .
  • a compound comprising a structure, wherein the structure interferes with expression of a cancer causing protein, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(O)-alkyl; and iii) guanidinoalkyl.
  • a compound comprising a structure, wherein the structure interferes with expression of a cancer causing protein , wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guani dinoalkyl.
  • a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(O)-alkyl; and iii) guani dinoalkyl.
  • a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl.

Abstract

The present disclosure relates to compounds and methods of modulating target nucleic acids that contain single nucleotide polymorphisms such as KRAS codon 12 mutations. Compounds disclosed herein can preferentially bind a sequence of nucleic acids encoding for a mutant Ras protein, thereby selectively modulating expression of the mutant protein.

Description

OLIGONUCLEOTIDE ANALOGUE MODULATORS OF ONCOGENES
CROSS REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application No. 63/197,798, filed June 7, 2021, and U.S. Provisional Application No. 63/250,062, filed September 29, 2021, each of which is entirely incorporated herein by reference.
BACKGROUND
[0002] Ras proteins are proto-oncogenes that are frequently mutated in human cancers. Ras proteins are encoded by three ubiquitously expressed genes: HRAS, KRAS, and NRAS. HRAS, KRAS, and NRAS are GTPases that function as molecular switches regulating pathways responsible for proliferation and cell survival. Aberrant Ras function is associated with hyperproliferative developmental disorders and cancer.
SUMMARY
[0003] In some embodiments, the present disclosure provides a compound comprising:
1) a pharmacophore, wherein the pharmacophore is a region that comprises a structure that interferes with expression of a cancer-causing protein; and
2) connected to the pharmacophore, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000003_0001
ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
[0004] In some embodiments, the present disclosure provides a compound comprising a structure that is:
Figure imgf000004_0001
wherein: the number of units with variables defined independently is at least 11;
N-Terminus is H, acyl, a group that together with the nitrogen atom to which the N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, O-alkyl, a peptide sequence, or NH2
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent;
LI is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof, wherein the compound interferes with expression of a cancer-causing protein. [0005] Additional aspects and/or advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and/or described. As will be realized, the present disclosure is capable of other and/or different embodiments, and/or its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and/or description are to be regarded as illustrative in nature, and/or not as restrictive.
INCORPORATION BY REFERENCE
[0006] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and/or advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and/or the accompanying drawings (also “figure” and “FIG.” herein), of which:
[0008] FIG. 1 illustrates in vivo tumor growth inhibition via RNA targeting of G12D mutation using Compound 1.
[0009] FIG. 2, Panel A illustrates the cell-signaling pathway downstream of RAS. Panels B-E illustrate reduction in aberrant signaling across multiple pathway members downstream of RAS, such as MEK (Panel B), ERK (Panel C), CREB (Panel D), and RSK3 (Panel E), using Compound 1.
[0010] FIG. 3 illustrates in vivo tumor growth inhibition via RNA targeting of G12V mutation using Compound 2.
[0011] FIG. 4 shows the effect of Compound 5 and Compound 6 on HPAFII tumor volume when administered at a dose of 0.3 μM, 3 μM, 10 μM, or 30 μM (IT; QWx3).
[0012] FIG. 5 shows the effect of Compound 5 and Compound 6 on body weight of mice inoculated with HPAFII cells when administered at a dose of 0.3 μM, 3 μM, 10 μM, or 30 μM (IT; QWx3).
[0013] FIG. 6 shows the effect of treatment on tumor volumes when animals were treated with vehicle, 0.1 mg/kg of Compound 6, and 0.3 mg/kg of Compound 6.
[0014] FIG. 7, Panel A shows results of an IYT assay using DNA coding for either wild type K-Ras or G12Y mutated K-Ras and treated with Compound 7 or Compound 8. Panel B shows the effect of treatment with Compound 7 or Compound 8 on tumor volumes in animals treated with 0 μM, 0.3 μM, 3 μM, 10 μM, or 30 μM of the compounds.
[0015] FIG. 8 shows the effect of treatment on tumor volumes when animals were treated with vehicle, 0.1 mg/kg of Compound 7, and 0.3 mg/kg of Compound 7.
[0016] FIG. 9, Panel A shows the effect of Compound 7 and Compound 9 on SHP-77 tumor volume when administered at a dose of 10 μM or 30 μM (IT). Panel B shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compound 7 and Compound 9.
[0017] FIG. 10 shows the effect of Compound 7 and Compound 9 on the body weight of mice inoculated with SHP-77 cells when administered at a dose of 10 μM or 30 μM (IT).
[0018] FIG. 11, Panel A shows the results of the cell viability assay of HPAF-II cells treated with 1 μM or 5 μM Compound 6 compared to controls (control cells untreated, HPAF-II; cells treated only with the transfection reagent Lipofectamine 2000, HPAF-II Lipo). Panel B shows cell cycle arrest results of HPAF-II cells treated with 1 μM or 5 μM Compound 6 compared to controls (control cells untreated, Mock; cells treated only with the transfection reagent Lipofectamine 2000, Lipo only).
[0019] FIG. 12, Panel A shows mRNA levels for KRAS alleles treated with Compound 6 as measured by qRT-PCR. Panel B shows G12D mutant KRAS protein levels when cells were treated with Compound 6 as measured by western blot.
[0020] FIG. 13, Panel A shows the results of the cell viability assay of Capan2 cells treated with 1 μM or 5 μM Compound 7 compared to controls (control cell untreated, Capan2; cells treated only with the transfection reagent Lipofectamine 2000, Capan2 Lipo). Panel B shows cell cycle arrest results of Capan2 cells treated with 1 pM or 5 pM Compound 7 compared to controls (control cell untreated, Mock; cells treated only with the transfection reagent Lipofectamine 2000, Lipo only).
[0021] FIG. 14, Panel A shows mRNA levels for KRAS alleles treated with Compound 7 as measured by qRT-PCR. Panel B shows G12V mutant KRAS protein levels when cells were treated with Compound 7 as measured by western blot.
[0022] FIG. 15, Panel A shows results of an IVT assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compound 51. Panel B shows the effect of treatment with Compound 51 on tumor volume in animals treated with control (PBS buffer); control (glucose buffer); 30 μM Compound 51 (PBS); 10 mg/kg Compound 51 (PBS); 30 μM Compound 51 (glucose buffer); or 10 mg/kg Compound 51 (glucose buffer).
[0023] FIG. 16, Panel A shows results of an SHP77 IVT assay using DNA coding for either wild type K-Ras or G12Y mutated K-Ras and treated with Compound 76 or Compound 90. Panel B shows the effect of treatment with Compound 76 or Compound 90 on tumor volume in animals treated with control (PBS vehicle); Compound 76 at 60 pM/dose; Compound 76 at 120 pM/dose; or Compound 90 at 120 pM/dose.
[0024] FIG. 17, Panel A shows results of a Capan2 IVT assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compound 76 or Compound 90. Panel B shows the effect of treatment with Compound 76 or Compound 90 on tumor volume in animals treated with glucose control; Compound 76 at 30 mg/kg; Compound 90 at 5 mg/kg; and Compound 90 at 30 mg/kg.
[0025] FIG. 18A, Panels A-D show that mice treated with Compounds 5 and 6 with HPAF-II tumors sacrificed on days 25-30 post-first dose exhibited decreased KRAS downstream signaling between 11 and 16 days post-last dose. Panel A shows G12D mutated K-Ras (RasG12D) relative to wild type K-Ras, Panel B shows G12V mutated K-Ras (RasG12V) relative to wild type K-Ras, Panel C shows P90RSK (via phospho-P90RSK T359/S363), and Panel D shows RSK3 (via phospho-RSK3 T356/S360).
[0026] FIG. 18B, Panels E-H show that mice treated with Compounds 5 and 6 with HPAF-II tumors sacrificed on days 25-30 post-first dose exhibited decreased KRAS downstream signaling between 11 and 16 days post-last dose. Panel E shows MEK (via phospho-MEKl/2 S217/S221), Panel F shows ERK (via phospho-ERK T202/Y204), Panel G shows MSK1 (via phospho-MSKl S360), and Panel H shows CREB (via phospho-CREB SI 33).
[0027] FIG. 19A, Panels A-D show the level of decreased KRAS signaling observed in SHP77 tumors treated with Compound 7 and Compound 9. Panel A shows G12D mutated K-Ras (RasG12D) relative to wild type K-Ras, Panel B shows G12V mutated K-Ras (RasG12V) relative to wild type K-Ras, Panel C shows P90RSK (via phospho-P90RSK T359/S363), and Panel D shows RSK3 (via phospho-RSK3 T356/S360).
[0028] FIG. 19B, Panels E-H show the level of decreased KRAS signaling observed in SHP77 tumors treated with Compound 7 and Compound 9. Panel E shows MEK (via phospho-MEKl/2 S217/S221), Panel F shows ERK (via phospho-ERK T202/Y204), Panel G shows MSK1 (via phospho-MSKl S360), and Panel H shows CREB (via phospho-CREB SI 33).
[0029] FIG. 20, Panels A-F show that no cell signaling differences were observed in KRAS downstream signaling pathways at 43 days post-first injection in Capan-2 xenograft tumors treated with Compound 7 or Compound 8. Panel A shows G12D mutated K-Ras (RasG12D), Panel B shows G12V mutated K-Ras (RasG12V), Panel C shows G12V mutated K-Ras (RasG12V) relative to wild type K-Ras, Panel D shows CREB (via phospho-CREB S133), Panel E shows MSK1 (via phospho-MSKl S360), and Panel F shows P90RSK (via phospho- P90RSK T359/S363).
[0030] FIG. 21, Panels A-E show that no cell signaling differences were observed in KRAS downstream signaling pathways at 43 days post-first injection in Capan-2 xenograft tumors treated with Compound 7 or Compound 8. Panel A shows G12D mutated K-Ras (RasG12D) relative to wild type K-Ras, Panel B shows wild type K-Ras, Panel C shows MEK (via phospho-MEKl/2 S217/S221), Panel D shows ERK (via phospho-ERK T202/Y204), and Panel E shows RSK3 (via phospho-RSK3 T356/S360).
[0031] FIG. 22, Panel A shows changes in mRNA levels of KRAS in A427 cells treated with control, Endo-Porter only, and Endo-Porter and Compound 6. Panel B shows changes in mRNA levels of KRAS in HPAF-II cells treated with control, Endo-Porter only, and Endo-Porter and Compound 6. Panel C shows changes in mRNA levels of KRAS in PANC1 cells treated with control, Endo-Porter only, and Endo-Porter and Compound 6.
[0032] FIG. 23, Panel A shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 5, 6, and 11-17. Panel B shows the results of an IVT assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compounds 7-9 and 18-29. Panel C shows the results of an IVT assay using DNA coding for either wild type K-Ras or G12C mutated K-Ras and treated with Compounds 30-42.
[0033] FIG. 24 shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 43-69.
[0034] FIG. 25, Panel A shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compounds 70-95. Panel B shows the results of an IVT assay using DNA coding for either wild type K-Ras or G12C mutated K-Ras and treated with Compounds 96-110.
[0035] FIG. 26, Panel A shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 204-220 at 0.5 μM. Panel B shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 204-220 at 0.25 μM.
[0036] FIG. 27 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e g. natural, modified, or non-natural nucleobases) or hydrogen.
[0037] FIG. 28 illustrates the structure of Compound 5.
[0038] FIG. 29 illustrates the structure of Compound 8.
[0039] FIG. 30 illustrates the structure of Compound 9. [0040] FIG. 31 illustrates the structure of Compound 11. [0041] FIG. 32 illustrates the structure of Compound 12. [0042] FIG. 33 illustrates the structure of Compound 26. [0043] FIG. 34 illustrates the structure of Compound 62. [0044] FIG. 35 illustrates the structure of Compound 63. [0045] FIG. 36 illustrates the structure of Compound 69. [0046] FIG. 37 illustrates the structure of Compound 71. [0047] FIG. 38 illustrates the structure of Compound 75. [0048] FIG. 39 illustrates the structure of Compound 76. [0049] FIG. 40 illustrates the structure of Compound 90. [0050] FIG. 41 illustrates the structure of Compound 93.
DETAILED DESCRIPTION
[0051] While various embodiments of the invention have been shown and/or described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and/or substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.
[0052] Ras proteins are proto-oncogenes that are frequently mutated in human cancers. Ras proteins are encoded by three ubiquitously expressed genes: HRAS, KRAS, and NRAS. HRAS, KRAS, and NRAS are GTPases that function as molecular switches regulating pathways responsible for proliferation and cell survival. Ras proteins are tightly regulated by guanine nucleotide exchange factors (GEFs) promoting GDP disassociation and GTP binding and GTP- ase activating proteins (GAPs) that stimulate the intrinsic GTPase activity of Ras to switch off signaling. Aberrant Ras function can be associated with hyper-proliferative developmental disorders and cancer, and Ras genes are among the earliest genes mutated in a variety of cancers.
[0053] HRAS, KRAS, and NRAS promote oncogenesis when mutationally activated at codons 12, 13, or 61. Mutations at the conserved sites favor GTP binding and produces constitutive activation of Ras. Ras isoforms share sequence identity in all the regions responsible for GDP/GTP binding, GTPase activity, and effector interactions suggesting functional redundancy. KRAS mutations are more frequently observed in cancer. Each ITRAS, KRAS, and NRAS isoform can display preferential coupling to particular cancer types. [0054] Disclosed herein are compounds and methods of targeting Ras mutations. In some embodiments, the compounds and methods of the disclosure can target codon 12 mutations. In some embodiments, the compounds and methods of the disclosure can target KRAS codon 12 mutations. In some embodiments, the KRAS codon 12 mutation is G12D. In some embodiments, the KRAS codon 12 mutation is G12V. In some embodiments, the compounds and methods of the disclosure can engage KRAS codon 12 mutations with allele-specific target engagement. In some embodiments, the compounds and methods of the disclosure can engage RNA to inhibit translation of KRAS codon 12 mutations. In some embodiments, the compounds and methods of the disclosure can engage DNA to inhibit translation of KRAS codon 12 mutations.
Compounds of the disclosure.
[0055] Provided herein are compounds that modulate (e.g., reduce) expression of one or more disease-causing Ras genes (e.g., HRAS, KRAS, and/or KRAS), and compositions thereof. In some embodiments, the present disclosure provides compounds that reduce expression of the disease-causing KRAS gene and compositions thereof. Selected compounds of the disclosure, corresponding target KRAS mutations, and target nucleic acids are provided in are provided in TABLE 1. Residue structures, pendant nucleobase identities (when present), and monomer chemical names associated with the symbols used in the structure codes of TABLE 1 are provided in TABLE 2. Compounds can be provided as a pharmaceutically-acceptable salt, tautomer, or ionized form thereof.
TABLE 1
Target PNA SEQ
Cpd # Structure Code (N to C terminus) a Target Nuc . SEQ ID Mut . Acid NOb’ NOc
1 CsCsTsAsCsGsCsCsAsTsCsAsGsCsTsCsCs G12D RNA 1 -
2 TsAnCsGnCsCnAsTnCsAnGsCnTsCnCsAnAs G12D RNA 2 -
3 TsAsCsGsCsCsAsTsCsAsGsCsTsCsCsAsAs G12D RNA 3 -
4 TsGsCsCsTsAsCsGsCsCsAsTsCsAsGsCsTs G12D RNA 4 -
GsCnCsTnAsCnGsCnCsAnTsCnAsGnCsTnCsCn 5
5 As An G12D RNA
GsCsCsTsAsCsGsCsCsAsTsCsAsGsCsTsCsCs 6
6 AsAs G12D RNA
TsGnCsCnTsAnCsGnCsCnAsAnCsAnGsCnTsCn 7
7 CsAn G12V RNA
8 CsTsAsCsGsCsCsAsAsCsAsGsCsTsCsCsAs G12V RNA 8 -
9 CsCnTsAnCsGnCsCnAsAnCsAnGsCnTsCnCs G12V RNA 9 -
11 CsTnAsCnGsCnCsAnTsCnAsGnCsTnCsCnAs G12D RNA 10 - a b
Figure imgf000011_0001
a b
Figure imgf000012_0001
a b
Figure imgf000013_0001
a b
Figure imgf000014_0001
a b
Figure imgf000015_0001
a b
Figure imgf000016_0001
a Ob
Figure imgf000017_0001
aUnless otherwise noted, all C-termini are amidated. bPortions of structure code not encompassed within braces correspond to the PNA SEQ NO provided in this column. cPortion of structure code within braces (e.g., {PKKKRKV}"), when present, correspond to SEQ ID NO provided in this column.
TABLE 2
Figure imgf000017_0002
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
aProteinogenic amino acid residues in compounds provided in TABLE 1 are represented by the following one-letter codes: A: Z-alanine, R: L-arginine, N: /.-asparagine, D: L -aspartic acid, C: L-cysteine, E: L-glutamic acid, Q: L-glutamine, G: glycine, H: L-histidine, I: L-isoleucine, L: L- leucine , K: L-lysine, M: L-methionine, F: L-phenylalanine, P: L-proline, S: L-serine, T: L- threonine, W: L-tryptophan, Y: L-tyrosine, V: L-valine. bAn antipode of a chiral residue presented in TABLE 2 is represented in TABLE 1 by the code of the chiral residue followed by an asterisk (*). For example, R* represents D -arginine. cFor each residue, a chemical name is provided for the corresponding unincorporated monomer. [0056] In some embodiments, the compound as disclosed herein can comprise a nucleic acid structure (e.g., a polynucleotide structure, a peptide nucleic acid (PNA) structure, or a combination thereof) exhibiting specific binding to a polynucleotide sequence of a Ras protein- encoding gene (e.g., HRAS, KRAS, and/or NRAS). The polynucleotide sequence can be a DNA sequence (e.g., a chromosomal DNA sequence) or an RNA (e.g., mRNA) sequence.
[0057] In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure comprises a gamma peptide nucleic acid residue that bears a hydroxyalkyl substituent. In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a mRNA sequence transcribed from a KRAS gene, wherein the peptide nucleic acid structure comprises at least 13 peptide nucleic acid residues. In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a mRNA sequence transcribed from a KRAS gene, wherein the peptide nucleic acid structure is attached to a sequence of at least 5 amino acid residues. In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure does not comprise a 1,4,7-tris(carboxymethylaza)cyclododecane-10-aza-acetyl group.
[0058] In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(0)-alkyl; and iii) guani dinoalkyl. In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl. In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid structure, wherein the peptide nucleic acid structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the peptide nucleic acid structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH. [0059] In some embodiments, the sequence of nucleic acids encoding the KRAS gene is an RNA (e.g., mRNA) sequence. In some embodiments, the sequence of nucleic acids encoding the KRAS gene is a DNA sequence.
[0060] Two-dimensional molecular structures of selected compounds of the disclosure are provided in Figures 28-41. FIG. 28 illustrates the structure of Compound 5. FIG. 29 illustrates the structure of Compound 8. FIG. 30 illustrates the structure of Compound 9. FIG. 31 illustrates the structure of Compound 11. FIG. 32 illustrates the structure of Compound 12.
FIG. 33 illustrates the structure of Compound 26. FIG. 34 illustrates the structure of Compound 62. FIG. 35 illustrates the structure of Compound 63. FIG. 36 illustrates the structure of Compound 69. FIG. 37 illustrates the structure of Compound 71. FIG. 38 illustrates the structure of Compound 75. FIG. 39 illustrates the structure of Compound 76. FIG. 40 illustrates the structure of Compound 90. FIG. 41 illustrates the structure of Compound 93.
[0061] In some embodiments, the disclosure provides a compound comprising a structure that is:
N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1-ξ-
Figure imgf000027_0001
wherein: the number of units with variables defined independently is at least 11;
N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralph a is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, OMe, or NH2;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent; PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent;
L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[0062] In some embodiments, the disclosure provides a compound comprising a structure that is:
N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1-£-
Figure imgf000028_0001
wherein: the number of units with variables defined independently is at least 11;
N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralph a is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least half of the R2 groups in the structure are independently methyl substituted with a heterocycle;
C-Terminus is OH, OMe, or NH2;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[0063] In some embodiments, the compound interferes with expression of a cancer-causing protein.
[0064] In some embodiments, each R2 is independently methyl substituted with a heterocycle. [0065] In some embodiments, the structure is:
Figure imgf000029_0001
wherein: the number of units with variables defined independently is at least 11;
N -Terminus is H, acyl, a group that together with the nitrogen atom to which /V-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralph a is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; and
C-Terminus is OH, OMe, NH2, or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
[0066] In some embodiments, the disclosure provides a compound comprising a structure that is:
Figure imgf000029_0002
wherein: the number of units with variables defined independently is at least 3;
N-Terminus is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, OMe, or NH2;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent; wherein at least one of PEP 1 and PEP2 is a peptide sequence of at least three amino acid residues,
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent;
L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[0067] In some embodiments, the number of units with variables defined independently is 17, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000030_0001
a second unit is present or absent, and in the second unit: R1 is H, -CH2OH, or 4-guanidinobut-l-yl; and R2 is a third unit is present, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl; and R2 is a fourth unit is present, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl; and R2 is a fifth unit is present, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl; and R2 is a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl; and R2 is a seventh unit is present, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl; and R2 is an eighth unit is present, and in the eighth unit:
Figure imgf000032_0004
a ninth unit is present, and in the ninth unit:
Figure imgf000032_0001
a tenth unit is present, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000032_0002
an eleventh unit is present, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000032_0003
a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000033_0001
thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000033_0002
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000033_0003
a sixteenth unit is present, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000033_0004
a seventeenth unit is present or absent, and in the seventeenth unit:
Figure imgf000034_0001
[0068] In some embodiments, the number of units with variables defined independently is 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000034_0002
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000034_0003
a third unit is present, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000034_0004
a fourth unit is present, and in the fourth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000035_0001
a fifth unit is present, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000035_0002
a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000035_0003
a seventh unit is present, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000035_0004
an eighth unit is present, and in the eighth unit: 1
Figure imgf000035_0005
a ninth unit is present, and in the ninth unit: 1
Figure imgf000036_0004
a tenth unit is present, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000036_0001
an eleventh unit is present, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000036_0002
a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000036_0003
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is a fourteenth unit is present, and in the fourteenth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000037_0001
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000037_0002
a sixteenth unit is present, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000037_0003
a seventeenth unit is present or absent, and in the seventeenth unit: 1
Figure imgf000037_0004
[0070] In some embodiments, the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000038_0001
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000038_0002
a third unit is present or absent, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000038_0003
a fourth unit is present or absent, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000038_0004
a fifth unit is present, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000038_0005
a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000038_0006
a seventh unit is present, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is an eighth unit is present, and in the eighth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is or a ninth unit is present, and in the ninth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is or a tenth unit is present, and in the tenth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000040_0001
a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000040_0002
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000040_0003
a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000040_0004
a fifteenth unit is present or absent, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000040_0005
a sixteenth unit is present or absent, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; a seventeenth unit is present or absent, and in the seventeenth unit:
[0071] R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000041_0001
[0072] In some embodiments, of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, and the seventeenth unit, independently if present, each have -CH2OH at R1.
[0073] In some embodiments, of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, and the seventeenth unit, independently if present, each have H at R1.
[0074] In some embodiments, of the units with variables defined independently, counting from N-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, and the seventeenth unit, independently if present, each have -CH2OH at R1.
[0075] In some embodiments, of the units with variables defined independently, counting from N-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, and the sixteenth unit, independently if present, each have H at R1.
[0076] In some embodiments, of the units with variables defined independently, counting from N-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, and the sixteenth unit, independently if present, each have - CH2OH at R1.
[0077] In some embodiments, of the units with variables defined independently, counting fromN-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, and the seventeenth unit, independently if present, each have H at R1.
[0078] In some embodiments, the disclosed herein is a compound of the formula above, wherein: in the first unit: R1 is H or -CH2OH; in the second unit: R1 is H or -CH2OH; in the third unit: R1 is H or -CH2OH; in the fourth unit: R1 is H or -CH2OH; in the fifth unit: R1 is H or - CH2OH; in the sixth unit: R1 is H or -CH2OH; in the seventh unit: R1 is H or -CH2OH; in the eighth unit: R1 is H or -CH2OH; in the ninth unit: R1 is H or -CH2OH; in the tenth unit: R1 is H or -CH2OH; in the eleventh unit: R1 is H or -CH2OH, in the twelfth unit: R1 is H or -CH2OH; in the thirteenth unit: R1 is H or -CH2OH; in the fourteenth unit: R1 is H or -CH2OH; in the fifteenth unit: R1 is H or -CH2OH; in the sixteenth unit: R1 is H or -CH2OH; and in the seventeenth unit: R1 is H or -CH2OH.
[0079] In some embodiments, the number of units with variables defined independently is 17, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000042_0001
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000042_0002
O) a third unit is present or absent, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000042_0003
a fourth unit is present or absent, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000042_0004
; or a fifth unit is present, and in the fifth unit: R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000043_0001
O a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl; and R2 is a seventh unit is present, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000043_0002
an eighth unit is present, and in the eighth unit: R2 is
Figure imgf000043_0004
a ninth unit is present, and in the ninth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000043_0003
Figure imgf000044_0001
a tenth unit is present, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000044_0002
an eleventh unit is present, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000044_0003
O a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000044_0004
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000044_0005
a fourteenth unit is present, and in the fourteenth unit: 1 O
Figure imgf000044_0006
a fifteenth unit is present or absent, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000045_0001
a sixteenth unit is present or absent, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000045_0002
a seventeenth unit is present or absent, and in the seventeenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000045_0003
[0080] In some embodiments, disclosed herein is a compound of the formula above, wherein: in the first unit: R1 is H or -CH2OH; in the second unit: R1 is H or -CH2OH; in the third unit: R1 is H or -CH2OH; in the fourth unit: R1 is H or -CH2OH; in the fifth unit: R1 is H or -CH2OH; in the sixth unit: R1 is H or -CH2OH; in the seventh unit: R1 is H or -CH2OH; in the eighth unit: R1 is H or -CH2OH; in the ninth unit: R1 is H or -CH2OH; in the tenth unit: R1 is H or -CH2OH; in the eleventh unit: R1 is H or -CH2OH; in the twelfth unit: R1 is H or -CH2OH; in the thirteenth unit: R1 is H or -CH2OH; in the fourteenth unit: R1 is H or -CH2OH; in the fifteenth unit: R1 is H or - CH2OH; in the sixteenth unit: R1 is H or -CH2OH; and in the seventeenth unit: R1 is H or -
CH2OH.
[0081] In some embodiments, the number of units with variables defined independently is 27, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000045_0004
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000046_0001
a third unit is present or absent, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000046_0002
a fourth unit is present or absent, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000046_0003
a fifth unit is present or absent, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000046_0004
a sixth unit is present or absent, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000046_0005
a seventh unit is present or absent, and in the seventh unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000047_0001
an eighth unit is present or absent, and in the eighth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000047_0002
a ninth unit is present or absent, and in the ninth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000047_0003
a tenth unit is present or absent, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000047_0004
an eleventh unit is present or absent, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000047_0005
a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000047_0006
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000048_0001
R2 is a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000048_0002
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000048_0003
a sixteenth unit is present, and in the sixteenth unit: 1
Figure imgf000048_0005
a seventeenth unit is present, and in the seventeenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000048_0004
an eighteenth unit is present, and in the eighteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000049_0001
a nineteenth unit is present, and in the nineteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000049_0002
a twentieth unit is present, and in the twentieth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000049_0003
a twenty-first unit is present, and in the twenty -first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000049_0004
a twenty-second unit is present or absent, and in the twenty-second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000049_0005
a twenty-third unit is present or absent, and in the twenty-third unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000050_0001
a twenty-fourth unit is present or absent, and in the twenty -fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000050_0002
a twenty-fifth unit is present or absent, and in the twenty-fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000050_0003
a twenty-sixth unit is present or absent, and in the twenty-sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000050_0004
a twenty-seventh unit is present or absent, and in the twenty-seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000050_0005
[0082] In some embodiments, the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, wherein: a first unit is present or absent, and in the first unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000051_0001
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000051_0002
a third unit is present or absent, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000051_0003
a fourth unit is present or absent, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000051_0004
a fifth unit is present or absent, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000051_0005
a sixth unit is present or absent, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000051_0006
a seventh unit is present or absent, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000052_0001
an eighth unit is present or absent, and in the eighth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000052_0002
a ninth unit is present or absent, and in the ninth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000052_0003
a tenth unit is present or absent, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000052_0004
an eleventh unit is present or absent, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000052_0005
a twelfth unit is present, and in the twelfth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000053_0001
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000053_0002
a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000053_0003
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000053_0004
R2 is O a sixteenth unit is present, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is or
Figure imgf000053_0005
a seventeenth unit is present, and in the seventeenth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000054_0001
O an eighteenth unit is present, and in the eighteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000054_0002
a nineteenth unit is present, and in the nineteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is
Figure imgf000054_0003
a twentieth unit is present, and in the twentieth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000054_0004
a twenty-first unit is present, and in the twenty -first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000054_0005
a twenty-second unit is present or absent, and in the twenty-second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000054_0006
a twenty-third unit is present or absent, and in the twenty-third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000055_0001
a twenty-fourth unit is present or absent, and in the twenty -fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is
Figure imgf000055_0002
a twenty-fifth unit is present or absent, and in the twenty-fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000055_0003
a twenty-sixth unit is present or absent, and in the twenty-sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000055_0004
a twenty-seventh unit is present or absent, and in the twenty-seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000055_0005
[0083] In some embodiments, of the units with variables defined independently, counting fromN-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the eighteenth unit, the nineteenth unit, the twentieth unit, the twenty-first unit, the twenty- second unit, the twenty -third unit, the twenty-fourth unit, the twenty -fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have -CH2OH at R1.
[0084] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty -first unit, the twenty -third unit, the twenty-fifth unit, and the twenty- seventh unit, independently if present, each have -CH2OH at R1.
[0085] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, the sixteenth unit, the eighteenth unit, the twentieth unit, the twenty-second unit, the twenty-fourth unit, and the twenty-sixth unit, independently if present, each have H at R1.
[0086] In some embodiments, of the units with variables defined independently, counting fromN-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, the sixteenth unit, the eighteenth unit, the twentieth unit, the twenty-second unit, the twenty-fourth unit, and the twenty-sixth unit, independently if present, each have -CH2OH at R1.
[0087] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty -first unit, the twenty -third unit, the twenty-fifth unit, and the twenty- seventh unit, independently if present, each have H at R1.
[0088] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the fourth unit, the eighth unit, the twelfth unit, the sixteenth unit, the twentieth unit, and the twenty -fourth unit, independently if present, each have -CH2OH at R1.
[0089] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the first unit, the second unit, the third unit, the fifth unit, the sixth unit, the seventh unit, the ninth unit, the tenth unit, the eleventh unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the seventeenth unit, the eighteenth unit, the nineteenth unit, the twenty-first unit, the twenty-second unit, the twenty -third unit, the twenty-fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R1.
[0090] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the eighteenth unit, and the nineteenth unit, independently if present, each have -CH2OH at R1. [0091] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the twentieth unit, the twenty -first unit, the twenty-second unit, the twenty -third unit, the twenty-fourth unit, the twenty-fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R1.
[0092] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the first unit, the third unit, the fourth unit, the fifth unit, the seventh unit, the eighth unit, the ninth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty- first unit, the twenty-third unit, the twenty-fourth unit, the twenty-fifth unit, and the twenty- seventh unit, independently if present, each have -CH2OH at R1.
[0093] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the second unit, the sixth unit, the tenth unit, the fourteenth unit, the eighteenth unit, the twenty-second unit, and the twenty-sixth unit, independently if present, each have H at R1.
[0094] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the fourth unit, the eighth unit, the twelfth unit, the sixteenth unit, the seventeenth unit, the twentieth unit, and the twenty-fourth unit, independently if present, each have -CH2OH atR1.
[0095] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the first unit, the second unit, the third unit, the fifth unit, the sixth unit, the seventh unit, the ninth unit, the tenth unit, the eleventh unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the eighteenth unit, the nineteenth unit, the twenty -first unit, the twenty-second unit, the twenty -third unit, the twenty -fifth unit, the twenty-sixth unit, and the twenty- seventh unit, independently if present, each have H at R1.
[0096] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the eighteenth unit, and the nineteenth unit, independently if present, each have -CH2OH at R1.
[0097] In some embodiments, of the units with variables defined independently, counting fromN-Terminus , the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the twentieth unit, the twenty -first unit, the twenty-second unit, the twenty -third unit, the twenty -fourth unit, the twenty-fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R1.
[0098] In some embodiments, disclosed herein is a compound of the formula above, wherein: in the first unit: R1 is H or -CH2OH; in the second unit: R1 is H or -CH2OH; in the third unit: R1 is H or -CH2OH; in the fourth unit: R1 is H or -CH2OH; in the fifth unit: R1 is H or -CH2OH; in the sixth unit: R1 is H or -CH2OH; in the seventh unit: R1 is H or -CH2OH; in the eighth unit: R1 is H or -CH2OH; in the ninth unit: R1 is H or -CH2OH; in the tenth unit: R1 is H or -CH2OH; in the eleventh unit: R1 is H or -CH2OH; in the twelfth unit: R1 is H or -CH2OH; in the thirteenth unit: R1 is H or -CH2OH; in the fourteenth unit: R1 is H or -CH2OH; in the fifteenth unit: R1 is H or - CH2OH; in the sixteenth unit: R1 is H or -CH2OH; in the seventeenth unit: R1 is H or -CH2OH; in the eighteenth unit: R1 is H or -CH2OH; in the nineteenth unit: R1 is H or -CH2OH; in the twentieth unit: R1 is H or -CH2OH; in the twenty-first unit: R1 is H or -CH2OH; in the twenty- second unit: R1 is H or -CH2OH; in the twenty-third unit: R1 is H or -CH2OH; in the twenty- fourth unit: R1 is H or -CH2OH; in the twenty-fifth unit: R1 is H or -CH2OH; in the twenty-sixth unit: R1 is H or -CH2OH; and in the twenty-seventh unit: R1 is H or -CH2OH.
[0099] In some embodiments, at least a third of the R2 groups in the structure are methyl substituted with a heterocycle. In some embodiments, at least half of the R2 groups in the structure are methyl substituted with a heterocycle. In some embodiments, the heterocycles of the R2 groups are nucleobases or analogues of nucleobases. In some embodiments, at least one of the heterocycles of the R2 groups is a divalent nucleobase. In some embodiments, the heterocycles of the R2 groups are divalent nucleobases. In some embodiments, the heterocycles of the R2 groups are each independently:
Figure imgf000059_0001
[00101] In some embodiments, PEP1 is absent. In some embodiments, PEP1 is the peptide sequence. In some embodiments, the peptide sequence of PEP 1 is a nuclear localization sequence. In some embodiments, PEP1 is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1). In some embodiments, PEP1 is Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2). In some embodiments, PEP1 is -Ala-Lys-Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 77). In some embodiments, PEP1 is -Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 78). In some embodiments, PEP1 is -Arg-Arg-. In some embodiments, PEP1 is -Arg-Phe-Gln-Ile-Leu-Tyr-Arg- (SEQ ID NO: 86). In some embodiments, PEP2 is absent. In some embodiments, PEP2 is the peptide sequence. In some embodiments, the peptide sequence of PEP2 is a nuclear localization sequence. In some embodiments, PEP2 is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1). In some embodiments, PEP2 is Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2). In some embodiments, PEP2 is -Arg-Arg-. In some embodiments, PEP2 is -Arg-Phe-Gln-Ile-Leu-Tyr- Arg- (SEQ ID NO: 86).
[00102] In some embodiments, SOL1 is absent. In some embodiments, SOL1 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL1 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL1 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOL1 is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL1 is a polyethyleneglycol group. In some embodiments, the water- solubilizing group of SOL1 is -Arg-Arg-NH(CH2)2C(0)-Arg-Arg-. [00103] In some embodiments, the sequence of nucleic acids encoding the KRAS gene is a mRNA sequence. In some embodiments, the sequence of nucleic acids encoding the KRAS gene is a DNA sequence.
[00104] In some embodiments, the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000060_0001
R1a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), orN(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00105] In some embodiments, the water-solubilizing group of SOLI is a group of formula:
Figure imgf000060_0002
wherein p is an integer that is 1-1,000. In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8. In some embodiments, p is an integer that is 7. [00106] In some embodiments, SOL2 is absent. In some embodiments, SOL2 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL2 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL2 is a polyethyleneglycol group. In some embodiments, the water- solubilizing group of SOL2 is -Arg-Arg-NH(CH2)2C(0)-Arg-Arg-. [00107] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000061_0001
R1a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), orN(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00108] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000061_0002
wherein p is an integer that is 1-1,000. In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8. In some embodiments, p is an integer that is 7. [00109] In some embodiments, PNA1 is the peptide nucleic acid sequence. In some embodiments, PNA2 is the peptide nucleic acid sequence. [00110] In some embodiments, L1 is the linker group. In some embodiments, the linker group of LI is cleavable. In some embodiments, the linker group of L1 is non-cleavable. In some embodiments, the linker group of L1 is a peptide sequence. In some embodiments, the linker group of L1 is a polyamine sequence. In some embodiments, the linker group of L1 is a polyamide sequence. In some embodiments, the linker group of L1 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L1 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L1 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L1 is a residue of oxalic acid. In some embodiments, the linker group of L1 is a residue of succinic acid. In some embodiments, the linker group of L1 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L1 is - NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L1 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L1 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L1 is - NH(CH2)5C(0)-. In some embodiments, the linker group of L1 is -NH(CH2)2C(0)-Arg- NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L1 is - NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0).
[00111] In some embodiments, L2 is the linker group. In some embodiments, the linker group of L2 is cleavable. In some embodiments, the linker group of L2 is non-cleavable. In some embodiments, the linker group of L2 is a peptide sequence. In some embodiments, the linker group of L2 is a polyamine sequence. In some embodiments, the linker group of L2 is a polyamide sequence. In some embodiments, the linker group of L2 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L2 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L2 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L2 is a residue of oxalic acid. In some embodiments, the linker group of L2 is a residue of succinic acid. In some embodiments, the linker group of L2 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L2 is - NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L2 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L2 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L2 is - NH(CH2)5C(0)-. In some embodiments, the linker group of L2 is -NH(CH2)2C(0)-Arg- NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L2 is - NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0).
[00112] In some embodiments, L3 is the linker group. In some embodiments, the linker group of L3 is cleavable. In some embodiments, the linker group of L3 is non-cleavable. In some embodiments, the linker group of L3 is a peptide sequence. In some embodiments, the linker group of L3 is a polyamine sequence. In some embodiments, the linker group of L3 is a polyamide sequence. In some embodiments, the linker group of L3 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L3 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L3 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L3 is a residue of oxalic acid. In some embodiments, the linker group of L3 is a residue of succinic acid. In some embodiments, the linker group of L3 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L3 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L3 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L3 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L3 is - NH(CH2)5C(0)-. In some embodiments, the linker group of L3 is -NH(CH2)2C(0)-Arg- NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L3 is - NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0).
[00113] In some embodiments, L4 is the linker group. In some embodiments, the linker group of L4 is cleavable. In some embodiments, the linker group of L4 is non-cleavable. In some embodiments, the linker group of L4 is a peptide sequence. In some embodiments, the linker group of L4 is a polyamine sequence. In some embodiments, the linker group of L4 is a polyamide sequence. In some embodiments, the linker group of L4 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L4 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L4 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L4 is a residue of oxalic acid. In some embodiments, the linker group of L4 is a residue of succinic acid. In some embodiments, the linker group of L4 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L4 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L4 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L4 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L4 is - NH(CH2)5C(0)-. In some embodiments, the linker group of L4 is -NH(CH2)2C(0)-Arg- NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L4 is - NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0).
[00114] In some embodiments, L5 is the linker group. In some embodiments, the linker group of L5 is cleavable. In some embodiments, the linker group of L5 is non-cleavable. In some embodiments, the linker group of L5 is a peptide sequence. In some embodiments, the linker group of L5 is a polyamine sequence. In some embodiments, the linker group of L5 is a polyamide sequence. In some embodiments, the linker group of L5 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L5 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L5 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L5 is a residue of oxalic acid. In some embodiments, the linker group of L5 is a residue of succinic acid. In some embodiments, the linker group of L5 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L5 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L5 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L5 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L5 is - NH(CH2)5C(0)-. In some embodiments, the linker group of L5 is -NH(CH2)2C(0)-Arg- NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L5 is - NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0).
[00115] In some embodiments, L6 is the linker group. In some embodiments, the linker group of L6 is cleavable. In some embodiments, the linker group of L6 is non-cleavable. In some embodiments, the linker group of L6 is a peptide sequence. In some embodiments, the linker group of L6 is a polyamine sequence. In some embodiments, the linker group of L6 is a polyamide sequence. In some embodiments, the linker group of L6 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L6 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L6 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L6 is a residue of oxalic acid. In some embodiments, the linker group of L6 is a residue of succinic acid. In some embodiments, the linker group of L6 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L6 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L6 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L6 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L6 is - NH(CH2)5C(0)-. In some embodiments, the linker group of L6 is -NH(CH2)2C(0)-Arg- NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L6 is - NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0).
[00116] In some embodiments, the structure is:
Figure imgf000064_0001
wherein: the number of units with variables defined independently is at least 3;
N-Terminu s is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each Ralph a is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; and
C-Terminus is OH, OMe, NH2, or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
[00117] In some embodiments, the structure is:
Figure imgf000065_0002
[00118] In some embodiments, the structure is:
N
Figure imgf000065_0003
[00119] In some embodiments, the disclosure provides a compound comprising a structure that is:
N-Terminus — L 1 — PEP 1 — L 2— SOL 1 — L 3 — PNA 1-
Figure imgf000065_0001
wherein: the first number of units with variables defined independently is at least zero; the second number of units with variables defined independently is at least 3; the third number of units with variables defined independently is at least zero;
N-Terminus is H, acyl, a group that together with the nitrogen atom to which A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R3 is independently a hydroxyalkyl group; each R4 is independently R2; each R5 is independently a group that is not hydroxyalkyl; each R6 is independently R2; each R7 is independently alkyl that is unsubstituted or substituted or H; each R8 is independently R2, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; each Ralpha1 is independently alkyl that is unsubstituted or substituted or H; each Ralpha2 is independently alkyl that is unsubstituted or substituted or H; each Ralpha3 is independently alkyl that is unsubstituted or substituted or H; each Ralpha4 is independently alkyl that is unsubstituted or substituted or H;
C-Terminus is OH, OMe, or NH2
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent;
L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[00120] In some embodiments, the first number of units with variables defined independently is 3-1,000. In some embodiments, the first number of units with variables defined independently is 3-100. In some embodiments, the first number of units with variables defined independently is 3-50. In some embodiments, the first number of units with variables defined independently is 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
In some embodiments, the first number of units with variables defined independently is at least 11. In some embodiments, the first number of units with variables defined independently is 11-
1,000. In some embodiments, the first number of units with variables defined independently is
11-100. In some embodiments, the first number of units with variables defined independently is 11-50. In some embodiments, the first number of units with variables defined independently is
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, the second number of units with variables defined independently is 3-1,000. In some embodiments, the second number of units with variables defined independently is 3-100. In some embodiments, the second number of units with variables defined independently is 3-50. In some embodiments, the second number of units with variables defined independently is 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, the second number of units with variables defined independently is 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, or 10.
[00121] In some embodiments, the third number of units with variables defined independently is 3-1,000. In some embodiments, the third number of units with variables defined independently is 3-100. In some embodiments, the third number of units with variables defined independently is 3-50. In some embodiments, the third number of units with variables defined independently is
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or
30. In some embodiments, the third number of units with variables defined independently is at least 11. In some embodiments, the third number of units with variables defined independently is 11-1,000. In some embodiments, the third number of units with variables defined independently is 11-100. In some embodiments, the third number of units with variables defined independently is 11-50. In some embodiments, the third number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, each R3 is hydroxymethyl. In some embodiments, each R5 is H.
[00122] In some embodiments, the disclosure provides a compound comprising a repeating unit of formula:
Figure imgf000068_0001
wherein: each R1 is independently a hydroxyalkyl group; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R3 is independently a group that is not hydroxyalkyl; each R4 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each Ralpha1 is independently alkyl that is unsubstituted or substituted or H; and each Ralpha2 is independently alkyl that is unsubstituted or substituted or H, wherein the repeating unit occurs at least twice consecutively in the compound.
[00123] In some embodiments, the disclosure provides a compound comprising: 1) a region that comprises a structure that interferes with expression of a cancer-causing protein; and 2) connected to the region that comprises the structure that interferes with expression of the cancer-causing protein, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000068_0002
or an ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
[00124] In some embodiments, the cancer-causing protein is H-ras, K-ras, or N-ras. In some embodiments, the cancer-causing protein is mutant K-ras. In some embodiments, the cancer- causing protein is G12D K-ras. In some embodiments, the cancer-causing protein is G12V K- ras. In some embodiments, the cancer-causing protein is G12C K-ras.
[00125] In some embodiments, the region that comprises the structure that interferes with expression of the cancer-causing protein binds to a nucleic acid sequence encoding a cancer gene. In some embodiments, the region that comprises the structure that interferes with expression of the cancer-causing protein binds to a mRNA sequence transcripted from a cancer gene. In some embodiments, the region that comprises the structure that interferes with expression of the cancer-causing protein binds to a mRNA sequence that encodes the cancer- causing protein. In some embodiments, the structure that interferes with expression of the cancer-causing protein is a peptide nucleic acid sequence.
[00126] In some embodiments, the disclosure provides a compound comprising:
1) a region that comprises a structure that interferes with expression of a cancer- causing protein; and
2) connected to the region that comprises the structure that interferes with expression of the cancer-causing protein, a compound comprising a repeating unit, wherein the repeating unit comprises: a) a guanidino group; b) a nitrogen atom that is bound to a -C(O)Me group and a -CH2C(O)- group; and c) a chain of carbon atoms, wherein the guanidino group is attached to the chain of carbon atoms at a first point of attachment; wherein the nitrogen atom is attached to the chain of carbon atoms at a second point of attachment; and wherein the first point of attachment and the second point of attachment are separated by 3-12 carbon atoms, or a pharmaceutically-acceptable salt or ionized form thereof.
[00127] In some embodiments, the disclosure provides a compound comprising:
1) a region that comprises a structure that interferes with expression of a cancer- causing protein; and
2) connected to the region that comprises the structure that interferes with expression of the cancer-causing protein, a compound of formula:
wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN);
E1 is a chemical moiety;
E2 is a chemical moiety; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000, or a pharmaceutically-acceptable salt or ionized form thereof.
[00128] In some embodiments, the present disclosure provides a peptide nucleic acid comprising a plurality of consecutive peptide nucleic acid monomers, wherein each peptide nucleic monomer of the plurality of consecutive peptide nucleic acid monomers comprises a gamma substituent, wherein each gamma substituent is independently hydroxyalkyl. In some embodiments, each gamma substituent is independently hydroxymethyl, 2-hydroxyeth-1-yl, 3- hydroxyprop-1-yl, or 4-hydroxybut-1-yl. In some embodiments, each gamma substituent is hydroxymethyl. In some embodiments, each gamma substituent is hydroxymethyl and the gamma carbon atom has a R-configuration. In some embodiments, a C-terminus of the peptide nucleic acid is ami dated.
[00129] In some embodiments, the present disclosure provides a compound that comprises a first peptide nucleic monomer that has a gamma substituent, wherein the first peptide nucleic acid monomer is linked via peptide bond to a second peptide nucleic acid monomer that does not have a gamma substituent, wherein the second peptide nucleic acid monomer is linked via a peptide bond to a third peptide nucleic acid monomer that has a gamma substituent, wherein the third peptide nucleic acid monomer is linked via a peptide bond to a fourth peptide nucleic acid monomer that does not have a gamma substituent. In some embodiments, each gamma substituent is independently hydroxyalkyl. In some embodiments, each gamma substituent is independently hydroxymethyl, n-hydroxy ethyl, or n-hydroxybutyl. In some embodiments, each gamma substituent is hydroxymethyl. In some embodiments, each gamma substituent is hydroxymethyl and the gamma carbon atom has a R-configuration.
[00130] In some embodiments, the present disclosure provides a compound that comprises a peptide nucleic acid domain, wherein the peptide nucleic acid domain comprises a first peptide nucleic monomer that has a gamma substituent, wherein the first peptide nucleic acid monomer is linked via peptide bond to a second peptide nucleic acid monomer that does not have a gamma substituent, wherein the second peptide nucleic acid monomer is linked via a peptide bond to a third peptide nucleic acid monomer that has a gamma substituent, wherein the third peptide nucleic acid monomer is linked via a peptide bond to a fourth peptide nucleic acid monomer that does not have a gamma substituent. In some embodiments, each gamma substituent is independently hydroxyalkyl. In some embodiments, each gamma substituent is independently hydroxymethyl, 2-hydroxyeth-1-yl, 3-hydroxyprop-1-yl, or 4-hydroxybut-1-yl. In some embodiments, each gamma substituent is hydroxymethyl. In some embodiments, each gamma substituent is hydroxymethyl and the gamma carbon atom has a R-configuration. In some embodiments, the peptide nucleic acid domain i
Figure imgf000071_0001
, wherein each of Bv and Bu are independently nucleobases, and q is from 2 to about 30.
[00131] In some embodiments, the compound further comprises a peptide domain, wherein the N-terminal end of the peptide domain is linked to the C-terminal end of the peptide nucleic acid domain via a peptide bond, wherein the peptide domain has a sequence according to SEQ ID NO 1. In some embodiments, the C-terminus of the compound is amidated. In some embodiments, the C-terminus of the compound is the C-terminus of the peptide domain.
[00132] In some embodiments, the compound further comprises a polyguanidyl domain linked to the peptide nucleic acid domain, wherein the polyguanidyl domain comprises a peptide nucleic acid backbone substituted with a plurality of guani dinoalkyl moieties. In some embodiments, the N-terminal end of the peptide nucleic acid domain is linked to the C-terminal end of the peptide nucleic acid of the polyguanidyl domain via a peptide bond. In some embodiments, the polyguanidyl moiety
Figure imgf000072_0001
, wherein each Rd is independently a guanidinoalkyl moiety of the plurality of guanidinoalkyl moieties; each Re is independently alkyl or acyl; and z is from 2 to about 30. In some embodiments, each Rd is independently 5- guanidino-pent-1-yl, 4-guanidino-but-l-yl, 3-guanidino-prop-1-yl, or 2-guanidino-ethyl-1-yl. In some embodiments, each Rd is 4-guanidino-but-l-yl. In some embodiments, each Re is independently acetyl, propanoyl, or butanoyl. In some embodiments, each Re is acetyl. In some embodiments, z is from 5-12. In some embodiments, z is 7.
[00133] FIG. 26 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e g. natural, modified, or non-natural nucleobases), or hydrogen. One or more oligonucleotide residues of a compound of the disclosure may be independently replaced with a residue comprising an alternative oligonucleotide backbone bearing an identical nucleobase. Nonlimiting examples of oligonucleotide backbones suitable for use in the present disclosure include phosphorothioate deoxyribonucleic acid (PS-DNA), boranophosphate DNA, alpha-, beta- constrained nucleic acid (α,β-CnA), 2'-methoxyribonucleic acid (2'-OMe-RNA), 2'- fluororibonucleic acid (2'-F-RNA), 2'-fluoroarabinonucleic acid (2'-F-ANA), sulfonyl-linked nucleic acid, methylene(methylimino) (MMI) linked, formacetal-linked nucleic acid, threose nucleic acid (TNA), 2'-methoxyribonucleic acid (2'-OMe-RNA), 2'-O-(2- methoxyethyl)ribonucleic acid (2'-MOE-RNA), unlocked nucleic acid (UNA), 2'-O,4'-C- ethylene-bridged nucleic acid (ENA), 2'-O,4'-C-propylene bridged nucleic acid (PrNA), bridged nucleic acids (e.g., 2',4'-BNACOC, 2',4'-BNANC[NH], 2',4'-BNANC[NMe], 3',4'-BNA), locked nucleic acid (LNA), bicylco[3.2.1]nucleic acid, (S )-constrained ethyl nucleic acid ((S)-cEt), hexitol nucleic acid (HNA), homo-deoxyribonucleic acid (hNDA), phosphorodiamidate morpholino oligomer (PMO), peptide nucleic acid (PNA), cyclohexene nucleic acid (CeNA), benzene phosphate backbone, tricyclo-DNA(tcDNA), glycol nucleic acid (GNA), and epimers and diastereomers thereof.
[00134] A compound of the disclosure (e.g. a peptide nucleic acid) can be conjugated to one or more polypeptides, such as a cell penetrating peptide, nuclear localization sequence, or other polypeptide that can facilitate uptake or cellular intake. Nonlimiting examples of cell- penetrating peptides include SV40 NLS (SEQ ID NO: 1: PKKKRKV), c-Myc NLS (SEQ ID NO: 2: PAAKRVKLD), nuleoplasmin (SEQ ID NO. 3: KRPAATKKAGQAKKKL), NF-Kb NLS (SEQ ID NO: 4: V QRKRQKLMP), TFIIE beta NLS (SEQ ID NO: 5: SKKKKTKV), Oct- 6 NLS (SEQ ID NO: 6: GRKRKKRT), HATF-3 NLS (SEQ ID NO 7: ERKKRRRE), SDC3 NLS (SEQ ID NO: 8: FKKFRKF), DPV3 (SEQ ID NO: 9: RKKRRRESRKKRRRES), DPV 6 (SEQ ID NO: 10: GRPRE S GKKRKRKRLKP), DPV7 (SEQ ID NO: 11 : GKRKKKGKLGKKRDP), DPV7b (SEQ ID NO: 12: GKRKKKGKLGKKRPRSR), DPV3/10 (SEQ ID NO: 13: RKKRRRESRRARRSPRHL), DPV10/6 (SEQ ID NO: 14: SRRARRSPRESGKKRKRKR), DPV1047 (SEQ ID NO: 15: VKRGLKLRHVRPRVTRMDV), DPV 10 (SEQ ID NO: 16: SRRARRSPRHLGSG), DPV15 (SEQ ID NO: 17:
LRRERQ SRLRRERQ SR), DPV15b (SEQ ID NO: 18: GAYDLRRRERQ SRLRRRERQSR), HIV-1 Tat (SEQ ID NO: 19: RKKRRQRRR), FHV coat (SEQ ID NO: 20: RRRRNRTRRNRRRVR), HIV-1 Rev (SEQ ID NO: 21: TRQARRNRRRRWRERQR), HTLV- II Rex (SEQ ID NO: 22: TRRQRTRRARRNR), BMV Gag (SEQ ID NO: 23: KMTRAQRRAAARRNRWTAR, P22 N (SEQ ID NO: 24 NAKTRRHERRRKLAIER), λN(1- 22) (SEQ ID NO: 25: MDAQTRRRERRAEKQAQWKAAN), φ21N(12-29) (SEQ ID NO: 26:
T AKTRYK ARRAELIAERR), Yeast Prp6 (SEQ ID NO: 27: TRRNKRNRIQEQLNRK), Protamine 1 (SEQ ID NO: 28: PRRRRS S SRP VRRRRRPRV SRRRRRRGGRRRR), Human cJun (SEQ ID NO: 29: RIKAERKRMRNRIAASKSRKRKLERIAR), Human cFos (SEQ ID NO: 30: KRRIRRERNKMAAAKSRNRRRELTDT), Yeast GCN4 (SEQ ID NO: 31 : KRARNTEAARRSRARKLQRMKQ), Penetratin (SEQ ID NO: 32:
RQIKIWF QNRRMKWKK), Islet-1 (SEQ ID NO: 33: RVIRVWF QNKRCKDKK), Fushi-tarazu (SEQ ID NO: 34:
SKRTRQT YTRY QTLELEKEFHFNRYITRRRRIDIANAL SL SERQIKIWF QNRRMKSKKDR ), Engrailed-2 (SEQ ID NO: 35: SQIKIWF QNKRAKIKK), HoxA-13 (SEQ ID NO: 36:
RQ VTIWF QNRRVKEKK), Knotted- 1 (SEQ ID NO: 37: KQINNWFINQRKRHWK), PDX-1 (SEQ ID NO: 38: RHIKIWFQNRRMKWKK), MPG (SEQ ID NO: 39:
GL AFLGFLGAAGSTMGAWSQPKKKRKV), Bac7 (SEQ ID NO: 40: RRIRPRPPRLPRPRPRPLPFPRPG), S413-PVrev (SEQ ID NO: 41: ALWKTLLKKVLKAPKKKRKV), HRSV (SEQ ID NO: 42: RRIPNRRPRR), L-2 (SEQ ID NO: 43: HARIKPTFRRLKWKYKGKFW), Melittin (SEQ ID NO: 44: GIGAVLKVLTTGLPALISWIKRKRQQ), SynB1 (SEQ ID NO: 45: RGGRLSYSRRRFSTSTGR), IVV-14 (SEQ ID NO: 46: KLWMRWY SPTTRRY G), AIP6 (SEQ ID NO: 47: RLRWR), CAYH (SEQ ID NO: 48: CAYHRLRRC), SVM4 (SEQ ID NO:
49: LYKKGPAKKGRPPLRGWFH), SVM3 (SEQ ID NO: 50: KGTYKKKLMRIPLKGT), SVM2 (SEQ ID NO: 51: RASKRDGSWVKKLHRILE), Buforin 2 (SEQ ID NO: 52: TRS SRAGLQWPVGRVHRLLRK), SVM1 (SEQ ID NO: 53: FKIYDKKVRTRVVKH), SAP (SEQ ID NO: 54: VRLPPPVRLPPPVRLPPP), 435b (SEQ ID NO: 55: GPFHFYQFLFPPV), Peptl (SEQ ID NO: 56: PLILLRLLRGQF ), YTA2 (SEQ ID NO: 57
YT AIAW VK AFIRKLRK), Pep-1 (SEQ ID NO: 58: KET WWET WWTEW S QPKKRK V), EB-1 (SEQ ID NO: 59: LIRE W SHLIHIWF QNRRLKWKKK), Pyrrho-coricin (SEQ ID NO: 60: VDKGSYLPRPTPPRPIYNRN), 439a (SEQ ID NO: 61: GSPW GLQHHPPRT), MAP (SEQ ID NO: 62: KLALKALKALKAALKLA), Bip (1) (SEQ ID NO: 63: IPALK), Bip (2) (SEQ ID NO: 64: VPALR), pVEC (SEQ ID NO: 65: LLIILRRRIRKQAHAFISK), YTA4 (SEQ ID NO: 66: IAWVKAFIRKLRKGPLG), K-FGF+NLS (SEQ ID NO: 67:
AA VLLP VLL AAP V QRKRQKLP), HN-1 (SEQ ID NO: 68: TSPLNIHNGQKL), Bip (3) (SEQ ID NO: 69: VPTLK), Bip (4) (SEQ ID NO: 70: VSALK), VT5 (SEQ ID NO: 71 : DPKGDPKGVTVTVTVTVTGKGDPKPD), Transportan 10 (SEQ ID NO: 72: AGYLLGKINLKALAALAKKIL), SAP(E) (SEQ ID NO: 73: VELPPPVELPPPVELPPP), CADY (SEQ ID NO: 74: GLWRALWRLLRSLWRLLWRA), PreS2-TLM (SEQ ID NO: 75: PLSSIFSRIGDP), R/W (SEQ ID NO: 76: RRWWRRWRR), Xentry (SEQ ID NO: 141: LCLRPVG), or combinations of any of the preceding.
[00135] In some embodiments, a compound of the disclosure is conjugated to a peptide that targets specific tissue, such as a muscle-targeting peptides. Suitable muscle targeting peptides can include, for example, MSP1 (SEQ ID NO: 77: AKASSLNIA), MSP2 (SEQ ID NO: 78: ASSLNIA), and A2G80 (SEQ ID NO: 79: VQLRNGFPYFSY).
[00136] In some embodiments, a compound of the disclosure is conjugated to a peptide that targets brain tissue. Suitable brain targeting peptides can include, for example, SEQ ID NO: 142: C(&)LS SRLD AC(&), SEQ ID NO: 143: C(&)AGALC(&)Y, SEQ ID NO: 144: C(&)LEVSRKNC(&), SEQ ID NO: 145: C(&)TSTSAPYC(&), SEQ ID NO: 146: c(&)MPRLRGC(&), and SEQ ID NO: 147: TGNYKALHPHNG.
[00137] Other peptides suitable for conjugation with a compound of the disclosure include transferrin receptor binders, such as THR (SEQ ID NO: 80: THRPPMWSPVWP) and HAI (SEQ ID NO: 81: HAIYPRH), as well as peptides that bind transferrin receptor-transferrin complex, such as CRT (SEQ ID NO: 82: C(&)RTIGPSVC(&)).
[00138] Retro-enantio analogues of any peptide disclosed herein are also suitable for conjugation to a compound of the present disclosure. A retro-enantio analogue can mimic the natural function of a corresponding parent peptide while exhibiting increased resistance to degradation. A retro-enantio analogue includes a peptide analogue where, relative to a parent peptide, both the linear peptide sequence and alpha-carbon chirality are inverted. For example, a retro-enantio analogue of THR (SEQ ID NO: 80: THRPPMWSPVWP) can be THRre (SEQ ID NO: 83: pwvpswmpprht), and a retro-enantio analogue of HAI (SEQ ID NO: 81: HAIYPRH) can be HAIre (SEQ ID NO: 84: hrpyiah), where lowercase one letter codes denote D-amino acid residues.
[00139] Enantiomers of any peptide disclosed herein are also contemplated, which enantiomers can include, for example, D-THR (SEQ ID NO: 85: thrppmwspvwp).
[00140] Other peptides suitable for conjugation with a compound of the disclosure include peptides consisting of or comprising sequences such as RFQILYR (SEQ ID NO: 86), RYQFLIR (SEQ ID NO: 87), RIQFLIR (SEQ ID NO: 88), RRWQW (SEQ ID NO: 89), GWWG (SEQ ID NO: 90), GFWFG (SEQ ID NO: 91), and GRKKRRQRRRPQ (SEQ ID NO: 92). Peptides comprising repeating units of charged residues are also contemplated, such as sequences comprising repeating units of contiguous arginine and glycine residues, such as (RG)e where e is from 1 to 50 (SEQ ID NO: 138) (e g. SEQ ID NO: 93: RGRGRGRGRGRGRG), polyarginine comprising from 2 to 100 contiguous arginine residues (SEQ ID NO: 139), (e.g. SEQ ID NO:
94: RRRRRRRRRRRR, and SEQ ID NO: 148: RRRRRRRR), and repeating units of proline- proline-arginine, such as (PPR)f where f is from 2 to 50 (SEQ ID NO: 140) (e.g., SEQ ID NO: 95: PPRPPRPPRPPR) .
[00141] In some embodiments, a compound of the disclosure is conjugated to a sequence derived from HIV-1 Tat, which can include, for example, RKKRRQRRR (SEQ ID NO: 19), YGRKKRRQRRR (SEQ ID NO: 149), and GRKKRRQ (SEQ ID NO: 150).
[00142] In some embodiments, sequence variants of the sequences described herein are contemplated. A variant typically differs from a sequence specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions. Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of sequences of the disclosure and evaluating one or more biological activities of the compounds as described herein. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid and/or nucleic acid sequences of the compound. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., modulation of a genetic target.
[00143] Percent (%) sequence identity with respect to a reference polypeptide or oligonucleotide sequence is the percentage of amino acid residues, nucleoside residues, and/or nucleoside analogue residues in a candidate sequence that are identical with residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared. In some embodiments, the degree of sequence identity between two sequences can be determined, for example, by comparing the two sequences using computer programs designed for this purpose, such as global or local alignment algorithms. Non-limiting examples include BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), BLASTp, BLASTn, Clustal W, MAFFT, Clustal Omega, AlignMe, Praline, GAP, BESTFIT, Needle (EMBOSS), Stretcher (EMBOSS), GGEARCH2SEQ, Water (EMBOSS), Matcher (EMBOSS), LALIGN, SSEARCH2SEQ, or another suitable method, software or algorithm. A global alignment algorithm, such as a Needleman and Wunsch algorithm, can be used to align two sequences over their entire length, maximizing the number of matches and minimizes the number of gaps. Default settings can be used. In some embodiments, % sequence identity values can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 program can be compiled for use on a UNIX operating system, including digital UNIX V4.0D. Sequences that can be compared by these algorithms include, for example, peptides, oligonucleotides, PNAs, and analogues of any of the foregoing.
[00144] When comparing two compounds that each have nucleobases or amino acid side chains but do not have the same backbone motif, the percent identity determination can be made based on comparison of the nucleobases or amino acid side chains. Residues in the two molecules being compared can be considered to share identity for the purpose of the percent identity analysis if the residues share a common nucleobase or amino acid side chain even if the residues have non-identical backbone structures. For example, Compound 58 and Compound 59 can be considered to share 100% nucleobase sequence identity.
[00145] Compounds disclosed herein can additionally comprise non-proteogenic acids in place of one or more proteogenic amino acids amino acids. Such non-proteogenic acids can include, for example, b-alanine, cystine, cystathionine, lanthionine, t-leucine, norleucine, homonorleucine, ornithine, allothreonine, homocysteine, citrulline, homoserine, isovaline, norvaline, sarcosine, N-ethyl glycine, N-propyl glycine, N-isopropyl glycine, N-methyl alanine, N-ethyl alanine, N-methyl b-alanine, N-ethyl b-alanine, and isoserine.
[00146] Compounds described herein can be associated with modifications of one or more amino acids of the compounds. Non-limiting examples of modifications include phosphorylation, acylation including acetylation and formylation, glycosylation (including N- linked and O-linked), amidation, hydroxylation, alkylation including methylation and ethylation, ubiquitination, addition of pyrrolidone carboxylic acid, formation of disulfide bridges, sulfation, myristoylation, palmitoylation, isoprenylation, farnesylation, geranylation, glypiation, lipoylation and iodination. [00147] The nucleobases within a PNA subunit can be naturally occurring or non-naturally occurring. Non-limiting examples of nucleobases include adenine, guanine, thymine, cytosine, uracil, pseudoisocytosine, 2-thiopseudoisocytosine, 5-methylcytosine, 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine (or 2,6-diaminopurine), 2-thiouracil, 2-thiothymine, 2- thiocytosine, 5-chlorouracil, 5-bromouracil, 5-iodouracil, 5-chlorocytosine,5-bromocytosine, 5- iodocytosine, 5-propynyl uracil, 5-propynyl cytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine, 7- deazaadenine, 3-deazaguanine, 3-deazaadenine, 7-deaza-8-aza guanine, 7-deaza-8-aza adenine, 5-propynyl uracil and 2-thio-5-propynyl, pyridazin-3(2H)-one (E), pyrimidin-2(1H)-one (P) and 2-aminopyridine (M), and tautomeric forms thereof.
[00148] Compounds disclosed herein can comprise divalent nucleobases. A divalent nucleobase can simultaneously bind specifically to two nucleic acid strands, whether or not the two strands are independent strands, two portions of a single strand (e.g., in a hairpin), or contain mismatches in the sense that at one or more positions within the two strands at the site of binding to the genetic recognition reagents, the bases are not able to base pair according to traditional Watson-Crick base pairing (A-T/U, T/U-A, G-C or C-G). Divalent nucleobases can be incorporated into a oligonucleotide analogue backbone such as those described in FIG. 20 (e.g. PNA monomer), which can then be incorporated into an oligomer of monomers with a desired sequence of nucleobases. TABLE 3 provides example divalent bases and their binding specificities, where R1 is hydrogen or a nitrogen protecting group and X is N or CH.
Nucleobase Target nucleobase pair Nucleobase residue
JBlc T(U)/D*
JBid T(U)/D*
JB2 D/T
‘
JB2b D/T(U)
JB3 G/C
JB3b G/C
JB4 C/G Nucleobase nucleobase Nucleobase
Figure imgf000079_0001
Nucleobase nucleobase Nucleobase
Figure imgf000080_0001
Nucleobase nucleobase Nucleobase
Figure imgf000081_0001
Nucleobase nucleobase Nucleobase
Figure imgf000082_0001
Nucleobase nucleobase Nucleobase
Figure imgf000083_0001
[00149] Compounds described herein (e.g., PNA subunits and PNA oligomers) can comprise one or more isotopic substitutions. For example, hydrogen can be in any isotopic form, including 'H (protium), 2H (D or deuterium), and 3H (T or tritium). Carbon can be in any isotopic form, including 12C, 13C, and 14C. Oxygen can be in any isotopic form, including 16O and 18O.
[00150] Compounds described herein (e.g., PNA subunits and PNA oligomers) can comprise one or more asymmetric centers, and can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods including chiral high-performance liquid chromatography (HPLC), selective crystallization as chiral salts, or in the presence of chiral hosts, or from chiral solvents, and through enrichment using enzymes or chemical processes such as dynamic kinetic resolution. A single isomer can be prepared by asymmetric synthesis. The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
Chemical Groups.
[00151] Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, hydrocarbyl groups, acyloxy groups, carbamate groups, amide groups, and ester groups.
[00152] Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups. An alkyl group can be, for example, a C1, C2, C3, C4, C5, C6,
C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted.
[00153] Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
[00154] Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec- butyl, and t-butyl.
[00155] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups. [00156] Non-limiting examples of alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups. The olefin or olefins of an alkenyl group can be, for example, E , Z, cis, trans, terminal, or exo-methylene. An alkenyl or alkenylene group can be, for example, a C2, C3, C4, Cs, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25,
C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46,
C47, C48, C49, or C50 group that is substituted or unsubstituted.
[00157] Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups. The triple bond of an alkylnyl or alkynylene group can be internal or terminal. An alkylnyl or alkynylene group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30,
C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted.
[00158] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
[00159] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or an ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy. [00160] An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be monocyclic or polycyclic. An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrdyl, pyridyl, imidazolyl, thiophenyl, and furyl. [00161] An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy.
[00162] An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl.
[00163] An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyl oxy.
[00164] A heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms. A heterocycle can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include nucleobases, pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
[00165] An acyl group can be, for example, a carbonyl group substituted with hydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle. Non-limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxy carbonyl, and ethoxy carbonyl.
[00166] An acyloxy group can be an oxygen atom substituted with an acyl group. An ester or an ester group comprises an acyloxy group. A non-limiting example of an acyloxy group, or an ester group, is acetate.
[00167] A carbamate group can be an oxygen atom substituted with a carbamoyl group, wherein the nitrogen atom of the carbamoyl group is unsubstituted, monosub stituted, or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form a heterocycle. [00168] A hydrocarbyl group can be any group consisting of carbon and hydrogen atoms, and can include alkyl groups, alkenyl groups, alkynyl groups, and aryl groups. A hydrocaryl group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group.
[00169] A hydrocarbylcarbonyl group can be a carbonyl group substituted with a hydrocarbyl group, which can be, for example, benzoyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undencanoyl, dodecanoyl, tridencanoyl, myristoyl, pentadecenoyl, palmitoyl, heptadecanoyl, stearoyl, nondecanoyl, arachidoyl, as well as acyl groups derived from saturated, monounsaturated, and polyunsaturated fatty acids, such as myristoleoyl, palmitoleoyl, sapienoyl, oleoyl, elaidoyl, vaccenoyl, linoleoyl, linoelaidoyl, a- linolenoyl, or arachidonoyl. A hydrocaryl carbonyl group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group.
[00170] An aminoalkylene group can be an alkyl group substituted with an amino group, such as, for example, aminom ethyl, 2-aminoeth-1-yl, 3-aminoprop-1-yl, 2-aminoprop-1-yl, 4- aminobut-1-yl, 3-aminobut-1-yl, 2-aminobut-1-yl, 5-aminopent-1-yl, 4-aminopent-1-yl, 4- aminopent-1-yl, 3-aminopent-1-yl, 2-aminopent-1-yl, a lysine side chain, or an ornithine side chain.
[00171] A guanidinoalkylene group can be an alkyl group substituted with a guanidino group, such as, for example, guanidinomethyl, 2-guanidinoeth-1-yl, 3-guanidinoprop-1-yl, 2- guanidinoprop-1-yl, 4-guanidinobut-1-yl, 3-guanidinobut-1-yl, 2-guanidinobut-1-yl, 5- guanidinopenty-1-1, 4-guanidinopent-1-yl, 4-guanidinopent-1-yl, 3-guanidinopent-1-yl, 2- guanidinopent-1-yl, an arginine side chain, or a homoarginine side chain.
[00172] Polypeptides and proteins disclosed herein (including functional portions and functional variants thereof) can comprise synthetic amino acids in place of one or more naturally-occurring amino acids. Such synthetic amino acids can include, for example, aminocyclohexane carboxylic acid, norleucine, α-amino n-decanoic acid, homoserine, S-acetylaminomethyl- cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4- chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine β-hydroxyphenylalanine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, 1,2, 3, 4-tetrahydroisoquinoline-3 -carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N'-benzyl-N' -methyl-lysine, N',N' -dibenzyl -lysine, 6-hydroxylysine, ornithine, α- aminocyclopentane carboxylic acid, a-aminocyclohexane carboxylic acid, a-aminocycloheptane carboxylic acid, α-(2-amino-2-norbomane)-carboxylic acid, α,γ-diaminobutyric acid, α,β- diaminopropionic acid, homophenylalanine, and α-tert-butylglycine.
[00173] In some embodiments, a compound of a disclosure bears one or more nitrogen protecting groups. Nonlimiting examples of nitrogen protecting groups include methyl, formyl, ethyl, acetyl, anisyl, benzyl, benzoyl, carbamate, trifluoroacetyl. diphenylmethyl, triphenylmethy , benzyloxymethyl, benzyloxycarbonyl, 2-nitrobenzoyl, t-Boc (tert- butyloxycarbonyl), 4-methylbenzyl, 4-nitrophenyl, 2-chorobenzyloxycarbonyl, 2- bromobenzyloxycarbonyl, 2,4,5-trichlorophenyL thioanizyl, thiocresyl, cbz (carbobenzyioxy), p- rnethoxybenzyl carbonyl, 9-fluorenylmetbyloxycarbonyl (Fmoc), pentafluorophenyl, p- methoxybenzyl, 3,4-dimethozybenzyl, p-methoxyphenyi, 4-toluenesuifonyl, p- nitrobenzenesul fonates, 9-fluorenylmethyl oxy carbonyl , 2-nitrophenylsulfenyl, 2, 2, 5,7,8- pentamethyl-chroman-6-sulfonyl, 2-(4-Ni tropheny I )sulfonylethoxy carbonyl (Nsc), 1,1- Dioxobenzo[b]thiophene-2-yimethyloxycarbonyl (Bsmoc), 1,1 ~Dioxonaphtho[ 1 ,2-b]thiophene- 2-methyloxy carbonyl (a-Nsraoc), 3,3-Dioxonapbtho[2,l-b]tbiopbene-2-methy3oxycarbonyl (β- Nsraoc), 1-(4,4~dimethyl-2,6-dioxocyciobex-l-yiidene)-3~methylbutyl (ivDde), 2,7-di-tert- butyl-9-fluorenylmethoxycarbonyl (Fmoc*), 2, -mono! sooctyI-9-fluorenylmethoxy carbonyl (mio Fmoc), 2,7-dii sooctyl -9-fluorenylmethoxy carbonyl, tetrachiorophthaloyl (TCP), 2-fluoro~9- fluorenylmethoxycarbonyl (Fmoc(2F)), 2-[Phenyl(methyl)sulfonio]ethyloxy carbonyl tetrafluoroborate (Pms), ethanesulfbnylethoxycarbonyl (Esc), 2-(4- suifophenylsulfonyl)ethoxycarbonyl (Sps), N,N-dim ethylaniinoxy carbonyl (Draaoc), and p- bromobenzenesulfonyl.
Pharmaceutically-acceptable salts.
[00174] The disclosure provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid- addition salts and base-addition salts. The acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically- acceptable salt is an ammonium salt.
[00175] Metal salts can arise from the addition of an inorganic base to a compound of the disclosure. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
[00176] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
[00177] Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, N-m ethyl pi peri dine, A-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.
[00178] In some embodiments, an ammonium salt is a triethyl amine salt, a trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-m ethyl morpholine salt, a piperidine salt, an JV-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.
[00179] Acid addition salts can arise from the addition of an acid to a compound of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, trifluoroacetic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.
[00180] In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a trifluoroacetate salt, a mandelate salt, a cinnamate salt, an aspartate salt, a stearate salt, a palmitate salt, a glycolate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt. [00181] Any compound herein can be purified. A compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.
[00182] In some embodiments, the compounds of the disclosure show non-lethal toxicity.
Therapeutic Methods
[00183] Compounds, compositions, and methods of the disclosure can be used to treat or ameliorate a condition of a subject (e.g., a human subject) in need thereof. Compounds, compositions, and methods of the disclosure can be used to modulate expression of a gene (e.g. a disease-causing gene, such as HRAS, KRAS, and/or NRAS) encoding a protein of the Ras subfamily (e.g. H-ras, K-ras, and/or N-ras). A compound disclosed herein can preferentially bind a sequence of nucleic acids encoding for a mutant Ras protein, thereby selectively modulating expression of the mutant protein. TABLE 4 provides nonlimiting examples of mutations that can be targeted by a compound of the disclosure, as well as associated conditions or diseases that can be treated by administration of a compound provided herein. In some embodiments, a compound of the disclosure is complementary to a nucleic acid sequence comprising a mutation selected from TABLE 4.
TABLE 4
Mutation Associated Phenotype Mutation Associated Phenotype urinary tract bladder carcinoma upper aerodigestive mouth cancer biliary tract bile duct carcinoma colorectal colon adenocarcinoma colorectal colon rectal adenocarcinoma endometrium carcinoma
H/L hematopoietic neoplasm
H/L lymphoid neoplasm lung adenocarcinoma bronchioloalveolar adenocarcinoma bronchioloalveolar non-small cell
KRAS carcinoma
G12A bronchioloalveolar squamous cell carcinoma ovary carcinoma pancreas ductal carcinoma pancreas adenoma pancreas dysplasia in situ neoplasm small intestine adenocarcinoma stomach adenocarcinoma thyroid carcinoma urinaiy tract bladder carcinoma upper aerodigestive mouth cancer biliary tract bile duct carcinoma gall bladder carcinoma colorectal colon adenocarcinoma colorectal colon rectal adenocarcinoma endometrium carcinoma
H/L hematopoietic neoplasm
H/L lymphoid neoplasm lung adenocarcinoma lung cancer bronchioloalveolar adenocarcinoma bronchioloalveolar non-small cell
KRAS carcinoma
G12C bronchioloalveolar squamous cell carcinoma ovary carcinoma pancreas ductal carcinoma pancreas PanIN pancreas adenoma pancreas borderline tumor pancreas chronic pancreatitis pancreas hyperplasia prostate adenocarcinoma skin carcinoma small intestine adenocarcinoma stomach adenocarcinoma thyroid carcinoma Mutation Associated Phenotype Mutation Associated Phenotype biliary tract bile duct carcinoma biliary tract bile duct carcinoma gall bladder carcinoma gall bladder carcinoma colorectal colon adenocarcinoma colorectal colon adenocarcinoma colorectal colon rectal colorectal colon rectal adenocarcinoma adenocarcinoma endometrium carcinoma endometrium carcinoma gastric cancer H/L hematopoietic neoplasm
H/L hematopoietic neoplasm H/L lymphoid neoplasm
H/L lymphoid neoplasm lung adenocarcinoma lung adenocarcinoma bronchioloalveolar adenocarcinoma bronchioloalveolar adenocarcinoma bronchioloalveolar non-small cell bronchioloalveolar non-small cell carcinoma carcinoma bronchioloalveolar squamous cell bronchioloalveolar squamous cell KRAS carcinoma carcinoma G12R ovary carcinoma juvenile myelomonocytic leukemia pancreas ductal carcinoma ovary carcinoma pancreas PanIN pancreatic carcinoma pancreas adenoma pancreas ductal carcinoma pancreas borderline tumor
KRAS pancreas PanIN pancreas chronic pancreatitis
G12D pancreas acinar-ductal metaplasia pancreas dysplasia in situ neoplasm pancreas adenoma pancreas hyperplasia pancreas autoimmune pancreatitis prostate adenocarcinoma pancreas borderline tumor skin malignant melanoma pancreas chronic pancreatitis stomach adenocarcinoma pancreas dysplasia in situ neoplasm thyroid carcinoma pancreas hyperplasia urinary tract bladder carcinoma prostate adenocarcinoma upper aerodigestive mouth cancer Ras-associated autoimmune biliary tract bile duct carcinoma leukoproliferative disorder gall bladder carcinoma Schimmelpennig-Feuerstein-Mims colorectal colon adenocarcinoma Syndrome colorectal colon rectal skin carcinoma adenocarcinoma skin malignant melanoma endometrium carcinoma small intestine adenocarcinoma H/L hematopoietic neoplasm somatic epidermal nevus H/L lymphoid neoplasm somatic sebaceous nevus lung adenocarcinoma stomach adenocarcinoma bronchioloalveolar adenocarcinoma thyroid carcinoma bronchioloalveolar non-small cell urinary tract bladder carcinoma carcinoma upper aerodigestive mouth cancer bronchioloalveolar squamous cell
KRAS KRAS carcinoma
G12F G12S ovary carcinoma pancreas ductal carcinoma pancreas adenoma pancreas chronic pancreatitis pancreas dysplasia in situ neoplasm pancreas hyperplasia prostate adenocarcinoma skin carcinoma skin malignant melanoma small intestine adenocarcinoma stomach adenocarcinoma thyroid carcinoma urinary tract bladder carcinoma upper aerodigestive mouth cancer Mutation Associated Phenotype Mutation Associated Phenotype biliary tract bile duct carcinoma biliary tract bile duct carcinoma gall bladder carcinoma gall bladder carcinoma colorectal colon adenocarcinoma colorectal colon adenocarcinoma colorectal colon rectal colorectal colon rectal adenocarcinoma adenocarcinoma endometrium carcinoma endometrium carcinoma gastric cancer H/L hematopoietic neoplasm
H/L hematopoietic neoplasm H/L lymphoid neoplasm
H/L lymphoid neoplasm lung adenocarcinoma lung adenocarcinoma bronchioloalveolar non-small cell bronchioloalveolar adenocarcinoma carcinoma bronchioloalveolar non-small cell KRAS bronchioloalveolar squamous cell carcinoma G13D carcinoma bronchioloalveolar squamous cell ovary carcinoma carcinoma pancreas ductal carcinoma
KRAS ovary carcinoma pancreas adenoma
G12V pancreatic carcinoma pancreas borderline tumor pancreas ductal carcinoma pancreas dysplasia in situ neoplasm pancreas PanIN prostate adenocarcinoma pancreas acinar-ductal metaplasia skin malignant melanoma pancreas adenoma small intestine adenocarcinoma pancreas borderline tumor stomach adenocarcinoma pancreas chronic pancreatitis thyroid carcinoma pancreas dysplasia in situ neoplasm urinary tract bladder carcinoma pancreas hyperplasia gall bladder carcinoma prostate adenocarcinoma colorectal colon adenocarcinoma skin carcinoma colorectal colon rectal skin malignant melanoma
KRAS adenocarcinoma small intestine adenocarcinoma G13 lung adenocarcinoma somatic sebaceous nevus R bronchioloalveolar non-small cell stomach adenocarcinoma carcinoma thyroid carcinoma thyroid carcinoma urinary tract bladder carcinoma urinary tract bladder carcinoma endometrium carcinoma biliary tract bile duct carcinoma lung adenocarcinoma colorectal colon adenocarcinoma
KRAS ovary carcinoma endometrium carcinoma
G13A thyroid carcinoma H/L lymphoid neoplasm urinary tract bladder carcinoma lung adenocarcinoma upper aerodigestive mouth cancer bronchioloalveolar non-small cell biliary tract bile duct carcinoma KRAS carcinoma colorectal colon adenocarcinoma G13S bronchioloalveolar squamous cell colorectal colon rectal carcinoma adenocarcinoma pancreas ductal carcinoma endometrium carcinoma prostate adenocarcinoma lung adenocarcinoma stomach adenocarcinoma
KRAS bronchioloalveolar adenocarcinoma thyroid carcinoma
G13C bronchioloalveolar non-small cell upper aerodigestive mouth cancer carcinoma colorectal colon adenocarcinoma ovary carcinoma colorectal colon rectal pancreas ductal carcinoma adenocarcinoma pancreas hyperplasia endometrium carcinoma stomach adenocarcinoma
KRAS lung adenocarcinoma thyroid carcinoma
G13V bronchioloalveolar non-small cell carcinoma ovary carcinoma pancreas adenoma small intestine adenocarcinoma stomach adenocarcinoma
KRAS
A18D
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000095_0002
Figure imgf000095_0001
Figure imgf000096_0002
Figure imgf000096_0001
[00184] In some embodiments, administration of a compound provided herein does not exhibit or substantially does not exhibit immunogenicity. In some embodiments, administration of a compound provided herein does not promote or substantially does not promote generation of neutralizing antibodies, complement factors, pro-inflammatory cytokines, or type 1 interferons upon or after administration of the compound to a subject. In some embodiments, a compound does not activate or substantially does not activate the TLR9 receptor and is not presented or is minimally presented by MHCI or MHCII complexes to the immune system.
[00185] Compounds provided herein can be locally or systemically administered to a subject in need thereof as a therapeutically-effective amount of a compound that binds to a sequence of nucleic acids encoding a cancer-causing protein (e.g., mutant K-ras). The subject can comprise a bloodstream, a brain, and a blood-brain-barrier. The compound that binds to the repeat codon can enter the brain by passing from the bloodstream through the blood-brain-barrier into the brain.
[00186] The present disclosure describes the use of a compound and methods of treating a condition. The method can comprise administering to the subject a therapeutically-effective amount of a compound of the disclosure. In some embodiments, the condition is a hematologic malignancy, for example, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or multiple myeloma (MM).
[00187] In some embodiments, compounds of the disclosure can be used to treat cancer in a subject. A compound of the disclosure can, for example, slow the proliferation of cancer cell lines, or kill cancer cells. Non-limiting examples of cancer that can be treated by a compound of the disclosure include: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas, Burkitt lymphoma, carcinoma of unknown primary origin, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing’s sarcoma, germ cell tumors, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gliomas, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, Hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liposarcoma, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, lymphomas, leukemias, macroglobulinemia, malignant fibrous histiocytoma of bone, medulloblastoma, melanomas, mesothelioma, metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndromes, myeloid leukemia, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pituitary adenoma, pleuropulmonary blastoma, plasma cell neoplasia, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas, skin cancers, skin carcinoma merkel cell, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, T-cell lymphoma, throat cancer, thymoma, thymic carcinoma, thyroid cancer, trophoblastic tumor (gestational), cancers of unknown primary site, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor.
[00188] In some embodiments, the compounds of the disclosure can treat a cancer associated with a KRAS mutation. In some embodiments, the cancer is cancer of the adrenal gland, autonomic ganglia, biliary tract, bone, breast, central nervous system, cervix, endometrium, hematopoietic/lymphoid, kidney, large intestine, liver, lung, esophagus, ovary, pancreas, prostate, salivary gland, skin, small intestine, stomach, testis, thymus, thyroid, upper aerodigestic tract, or urinary tract. In some embodiments, the cancer is cancer of the biliary tract. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is cancer of the large intestine. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is cancer of the small intestine.
[00189] In some embodiments, the compounds and methods of the disclosure target a cancer with a HRAS mutation. In some embodiments, the HRAS mutation is a codon 12 mutation. In some embodiments, the HRAS codon 12 mutation is G12A, G12C, G12D, G12R, G12S, or G12V. In some embodiments, the HRAS codon 12 mutation is G12V. In some embodiments, the HRAS mutation is a codon 13 mutation. In some embodiments, the HRAS codon 13 mutation is G13C, G13D, G13R, G13S, or G13V. In some embodiments, the HRAS codon 13 mutation is G13R. In some embodiments, the HRAS mutation is a codon 61 mutation. In some embodiments, the HRAS codon 61 mutation is Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the HRAS codon 61 mutation is Q61R. In some embodiments, the cancer is a dermatological cancer with an HRAS codon mutation. In some embodiments, the cancer is a head and neck cancer with an HRAS codon mutation.
[00190] In some embodiments, the compounds and methods of the disclosure target a cancer with a KRAS mutation. In some embodiments, the KRAS mutation is a codon 12 mutation. In some embodiments, the KRAS codon 12 mutation is G12A, G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS codon 12 mutation is G12D. In some embodiments, the KRAS mutation is a codon 13 mutation. In some embodiments, the KRAS codon 13 mutation is G13A, G13C, G13D, G13R, G13S, or G13V. In some embodiments, the KRAS codon 13 mutation is G13D. In some embodiments, the KRAS mutation is a codon 61 mutation. In some embodiments, the KRAS codon 61 mutation is Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the KRAS codon 61 mutation is Q61H. In some embodiments, the cancer is pancreatic carcinoma with a KRAS codon mutation. In some embodiments, the cancer is colorectal cancer with a KRAS codon mutation. In some embodiments, the cancer is a lung cancer with a KRAS codon mutation.
[00191] In some embodiments, the compounds and methods of the disclosure target a cancer with a NRAS mutation. In some embodiments, the NRAS mutation is a codon 12 mutation. In some embodiments, the NRAS codon 12 mutation is G12A, G12C, G12D, G12R, G12S, or G12V. In some embodiments, the NRAS codon 12 mutation is G12D. In some embodiments, the NRAS mutation is a codon 13 mutation. In some embodiments, the NRAS codon 13 mutation is G13A, G13C, G13D, G13R, G13S, or G13V. In some embodiments, the NRAS codon 13 mutation is G13D. In some embodiments, the NRAS mutation is a codon 61 mutation. In some embodiments, the NRAS codon 61 mutation is Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the NRAS codon 61 mutation is Q61R. In some embodiments, the cancer is a melanoma with an NRAS codon mutation. In some embodiments, the cancer is a hematopoietic malignancy with an NRAS codon mutation.
[00192] In some embodiments, a compound of the disclosure binds to the nucleobase that corresponds to the nucleotide polymorphism of the non-wild type RAS gene of a subject. In some embodiments, a compound of the disclosure binds to the nucleobase that corresponds to the nucleotide polymorphism of the non-wild type HRAS gene of a subject. In some embodiments, a compound of the disclosure binds to the nucleobase that corresponds to the nucleotide polymorphism of the non-wild type KRAS gene of a subject. In some embodiments, a compound of the disclosure binds to the nucleobase that corresponds to the nucleotide polymorphism of the non-wild type NRAS gene of a subject. [00193] In some embodiments, a compound of the disclosure binds to an RNA (e.g., mRNA) sequence transcribed from a non-wild type RAS gene. In some embodiments, a compound of the disclosure binds to an mRNA sequence transcribed from a non-wild type KRAS gene. In some embodiments, a compound of the disclosure binds to an mRNA sequence transcribed from a non-wild type HRAS gene. In some embodiments, a compound of the disclosure binds to an mRNA sequence transcribed from a non-wild type NRAS gene.
[00194] In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a cancer gene. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a cancer-causing protein. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a non-wild type RAS gene. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a non-wild type KRAS gene. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a non-wild type HRAS gene. In some embodiments, a compound of the disclosure binds to a DNA sequence encoding a non-wild type NRAS gene.
[00195] In some embodiments, administration of a compound of the disclosure does not exhibit immunogenicity. In some embodiments, administration of a compound of the disclosure does not promote generation of neutralizing antibodies, complement factors, pro-inflammatory cytokines, or type 1 interferons upon or after administration of the compound to a subject. In some embodiments, the compounds do not activate the TLR9 receptor and are not presented in MHCI or MHCII complexes to the immune system.
Therapeutic Effects
Tumor Volume.
[00196] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
[00197] In some embodiments, if, in a 22 day study, a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 10 mm3; on day 5 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 60 mm3 to about 80 mm3; on day 8 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 130 mm3 to about 150 mm3; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 360 mm3 to about 390 mm3; on day 15 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 420 mm3 to about 450 mm3; on day 19 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 540 mm3 to about 580 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 600 mm3 to about 720 mm3.
[00198] In some embodiments, if in a 22 day study, a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 10 mm3; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 360 mm3 to about 390 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 600 mm3 to about 720 mm3.
[00199] In some embodiments, if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 10 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 600 mm3 to about 720 mm3.
[00200] In some embodiments, if, in a 22 day study, a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm3 to about 120 mm3, and a mean tumor volume size in the test group is observed to be from about 80 mm3 to about 120 mm3; on day 5 of the study, a mean tumor volume size in the control group is determined to be from about 210 mm3 to about 250 mm3, and a mean tumor volume size in the test group is observed to be from about 140 mm3 to about 180 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 400 mm3 to about 470 mm3, and a mean tumor volume size in the test group is observed to be from about 250 mm3 to about 320 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 940 mm3, and a mean tumor volume size in the test group is observed to be from about 390 mm3 to about 550 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 1000 mm3 to about 1180 mm3, and a mean tumor volume size in the test group is observed to be from about 550 mm3 to about 770 mm3; on day 19 of the study, a mean tumor volume size in the control group is determined to be from about 1220 mm3 to about 1680 mm3, and a mean tumor volume size in the test group is observed to be from about 750 mm3 to about 1020 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 1450 mm3 to about 2000 mm3, and a mean tumor volume size in the test group is observed to be from about 900 mm3 to about 1210 mm3.
[00201] In some embodiments, if in a 22 day study, a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm3 to about 120 mm3, and a mean tumor volume size in the test group is observed to be from about 80 mm3 to about 120 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 940 mm3, and a mean tumor volume size in the test group is observed to be from about 390 mm3 to about 550 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 1450 mm3 to about 2000 mm3, and a mean tumor volume size in the test group is observed to be from about 900 mm3 to about 1210 mm3.
[00202] In some embodiments, if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm3 to about 120 mm3, and a mean tumor volume size in the test group is observed to be from about 80 mm3 to about 120 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 1450 mm3 to about 2000 mm3, and a mean tumor volume size in the test group is observed to be from about 900 mm3 to about 1210 mm3.
[00203] In some embodiments, the compound is a DNA binding agent.
[00204] In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
[00205] In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the KRAS gene, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the KRAS gene.
[00206] In some embodiments, the peptide nucleic acid sequence is complementary to the nonwild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene.
[00207] In some embodiments, the peptide nucleic acid sequence is complementary to the nonwild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism.
[00208] In some embodiments, the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the gene. [00209] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a DNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence. [00210] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene.
[00211] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene. [00212] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T).
[00213] In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
[00214] In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non- wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the nonwild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism.
[00215] In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to the non-wild type gene over the wild-type gene. In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene.
[00216] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
[00217] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence transcribed from the non-wild type gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
[00218] In some embodiments, the compound reduces transcription of the non-wild type KRAS gene. In some embodiments, the compound reduces translation of the mRNA sequence transcribed from the non- wild type gene.
[00219] In some embodiments, the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma.
[00220] In some embodiments, the human cancer associated with the non-wild type KRAS gene is pancreatic cancer. In some embodiments, the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II.
[00221] In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A).
[00222] In some embodiments, the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the nonwild type K-ras protein is K-ras G12C.
[00223] In some embodiments, the mice are SCID mice.
[00224] In some embodiments, the compound has the formula:
Figure imgf000107_0001
wherein each B is independently the nucleobase of the plurality of nucleobase-bearing side chains, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, thymine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, adenine, or a pharmaceutically acceptable salt or ionized form thereof.
[00225] In some embodiments, the compound has the formula:
Figure imgf000107_0002
wherein each of B1 and B2 is independently the nucleobase of the plurality of nucleobase-bearing side chains, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: thymine, guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, adenine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, or a pharmaceutically acceptable salt or ionized form thereof Oncogenic Signaling.
[00226] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid sequence associated with a non-wild type KRAS gene, wherein if, in a study: a) i) a test SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF- II cells by subcutaneous injection, and a tumor having a volume of about 100 mm3 forms in the test SCID mouse; ii) after the tumor forms, the test SCID mouse is dosed intratumorally once per week for three consecutive weeks with the compound in a vehicle at one of 0.3 μM, 1 μM, 3 pM, 10 μM, and 30 μM; iii) after the three consecutive weeks, the test SCID mouse is monitored until the tumor that forms in the test SCID mouse has a volume of about 1,500 mm3; iv) after the tumor that forms in the test SCID mouse reaches a volume of about 1,500 mm3, a sample of the tumor is harvested, frozen, and laser microdissected while frozen to provide a section of the tumor that forms in the test SCID mouse; and v) the section of the tumor that forms in the test SCID mouse is analyzed by reverse phase protein array to quantify an amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse; and b) i) a control SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF-II cells by subcutaneous injection, and a tumor having a volume of about 100 mm3 forms in the control SCID mouse; ii) after the tumor forms, the control SCID mouse is dosed intratumorally once per week for three consecutive weeks with the vehicle; iii) after the three consecutive weeks, the control SCID mouse is monitored until the tumor that forms in the control SCID mouse has a volume of about 1,500 mm3; iv) after the tumor that forms in the control SCID mouse reaches a volume of about 1,500 mm3, a sample of the tumor is harvested, frozen, and laser microdissected while frozen to provide a section of the tumor that forms in the control SCID mouse; and v) the section of the tumor that forms in the control SCID mouse is analyzed by reverse phase protein array to quantify an amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse, then the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be at most about 70% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
[00227] In some embodiments, the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be at most about 60% of the amount of phospho- MEK in the section of the tumor that forms in the control SCID mouse.
[00228] In some embodiments, the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be at most about 55% of the amount of phospho- MEK in the section of the tumor that forms in the control SCID mouse.
[00229] In some embodiments, the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be about 40% to about 60% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
[00230] In some embodiments, the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be about 40% to about 50% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
[00231] In some embodiments, the peptide nucleic acid sequence binds to a mRNA sequence transcribed from the non- wild type KRAS gene.
[00232] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid sequence associated with a non-wild type KRAS gene, wherein if, in a study: a) i) a test SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF- II cells by subcutaneous injection, and a tumor having a volume of about 100 mm3 forms in the test SCID mouse; ii) after the tumor forms, the test SCID mouse is dosed intratumorally once per week for three consecutive weeks with the compound in a vehicle at one of 0.3 μM , 1 μM, 3 μM, 10 μM, and 30 μM; iii) after the three consecutive weeks, the test SCID mouse is monitored until the tumor that forms in the test SCID mouse has a volume of about 1,500 mm3; iv) after the tumor that forms in the test SCID mouse reaches a volume of about 1,500 mm3, a sample of the tumor is harvested, frozen, and laser microdissected while frozen to provide a section of the tumor that forms in the test SCID mouse; and v) the section of the tumor that forms in the test SCID mouse is analyzed by reverse phase protein array to quantify an amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse; and b) i) a control SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF-II cells by subcutaneous injection, and a tumor having a volume of about 100 mm3 forms in the control SCID mouse; ii) after the tumor forms, the control SCID mouse is dosed intratumorally once per week for three consecutive weeks with the vehicle; iii) after the three consecutive weeks, the control SCID mouse is monitored until the tumor that forms in the control SCID mouse has a volume of about 1,500 mm3; iv) after the tumor that forms in the control SCID mouse reaches a volume of about 1,500 mm3, a sample of the tumor is harvested, frozen, and laser microdissected while frozen to provide a section of the tumor that forms in the control SCID mouse; and v) the section of the tumor that forms in the control SCID mouse is analyzed by reverse phase protein array to quantify an amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse, then the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 50% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
[00233] In some embodiments, the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 40% of the amount of phospho- CREB in the section of the tumor that forms in the control SCID mouse.
[00234] In some embodiments, the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 30% of the amount of phospho- CREB in the section of the tumor that forms in the control SCID mouse.
[00235] In some embodiments, the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be from about 10% to about 30% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
[00236] In some embodiments, the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be from about 15% to about 25% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
[00237] In some embodiments, the peptide nucleic acid sequence binds to a mRNA sequence transcribed from the non- wild type KRAS gene.
[00238] In some embodiments, the compound has the formula:
Figure imgf000110_0001
wherein each B is independently a nucleobase, wherein the peptide nucleic acid sequence has a nucleobase sequence that is guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, thymine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, adenine, or a pharmaceutically acceptable salt or ionized form thereof.
[00239] In some embodiments, the compound has the formula:
Figure imgf000110_0002
wherein each of B1 and B2 is independently a nucleobase, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: thymine, guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, adenine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, or a pharmaceutically acceptable salt or ionized form thereof.
K-ras Expression.
[00240] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
[00241] In some embodiments, if, in a study: a) a first assay is performed to determine a mean in vitro expression of the wild type K- ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about 1 mM of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K-ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the wild type K-ras protein in the sample by quantifying the luminescence; b) a second assay is performed to determine a mean in vitro expression of the non-wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the non-wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about 1 mM of the compound to produce an amount of the non-wild type K-ras protein, wherein the amount of the non-wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the non-wild type K-ras protein, contacting the non-wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the non-wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the non-wild type K-ras protein in the sample by quantifying the luminescence; c) a first control experiment is performed to determine a mean control in vitro expression of the wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in absence of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K-ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the wild type K-ras protein in the sample by quantifying the luminescence; and d) a second control experiment is performed to determine a mean control in vitro expression of the non-wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the non-wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in absence of the compound to produce an amount of the non-wild type K-ras protein, wherein the amount of the non-wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the non-wild type K-ras protein, contacting the non-wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the non-wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the non-wild type K-ras protein in the sample by quantifying the luminescence, then: i) the mean in vitro expression of the wild type K-ras protein is determined to be within 5% of the mean control in vitro expression of the wild type K-ras protein; ii) the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 10% lesser than is the mean control in vitro expression of the non-wild type K-ras protein; and iii) the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 10% lesser than is the mean in vitro expression of the wild type K-ras protein.
[00242] In some embodiments, the mean in vitro expression of the wild type K-ras protein is determined to be within 1% of the mean control in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean control in vitro expression of the non-wild type K-ras protein.
[00243] In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean in vitro expression of the wild type K-ras protein.
[00244] In some embodiments, the non-wild type K-ras protein is K-ras G12D In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non- wild type K-ras protein is K-ras G12C. In some embodiments, the compound is a DNA binding agent. In some embodiments, the compound comprises a gamma-peptide nucleic acid. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism. In some embodiments, the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a DNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
[00245] In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T).
[00246] In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence that arises from transcription of the non-wild type KRAS gene over a mRNA sequence that arises from transcription of the wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non- wild-type KRAS gene at the single nucleotide polymorphism. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the compound reduces transcription of the non-wild type KRAS gene. In some embodiments, the compound reduces translation of the mRNA sequence transcribed from the non- wild type KRAS gene.
[00247] In some embodiments, the condition is a human cancer. In some embodiments, the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma. In some embodiments, the human cancer associated with the non-wild type KRAS gene is pancreatic cancer. In some embodiments, the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II. In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
[00248] In some embodiment, the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
[00249] In some embodiments, if, in a study: a) a first assay is performed to determine a mean in vitro expression of the wild type K- ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about ImM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about ImM of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K- ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the wild type K-ras protein in the sample by quantifying the luminescence; b) a second assay is performed to determine a mean in vitro expression of the non-wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the non-wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about ImM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about ImM of the compound to produce an amount of the non-wild type K-ras protein, wherein the amount of the non-wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the non-wild type K-ras protein, contacting the non-wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the non-wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the non-wild type K-ras protein in the sample by quantifying the luminescence; c) a first control experiment is performed to determine a mean control in vitro expression of the wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about 1 mM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in absence of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K-ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the wild type K-ras protein in the sample by quantifying the luminescence; and d) a second control experiment is performed to determine a mean control in vitro expression of the non-wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the non-wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about 1 mM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in absence of the compound to produce an amount of the non-wild type K- ras protein, wherein the amount of the non-wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the non-wild type K-ras protein, contacting the non-wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the non-wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the non-wild type K-ras protein in the sample by quantifying the luminescence, then: i) the mean in vitro expression of the wild type K-ras protein is determined to be within 30% of the mean control in vitro expression of the wild type K-ras protein; ii) the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 10% lesser than is the mean control in vitro expression of the non-wild type K-ras protein; and iii) the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 10% lesser than is the mean in vitro expression of the wild type K-ras protein.
[00250] In some embodiments, the mean in vitro expression of the wild type K-ras protein is determined to be within 5% of the mean control in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean control in vitro expression of the no- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean control in vitro expression of the nonwild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 65% lesser than to about 95% lesser than the mean control in vitro expression of the non-wild type K-ras protein. [00251] In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non- wild type K-ras protein is determined to be about 65% lesser than to about 95% lesser than the mean in vitro expression of the wild type K-ras protein.
[00252] In some embodiments, the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non- wild type K-ras protein is K-ras G12C.
[00253] In some embodiments, the compound is a nucleic acid binding agent. In some embodiments, the compound is a DNA binding agent. In some embodiments, the compound is a RNA binding agent. In some embodiments, the compound is a mRNA binding agent. In some embodiments, the compound comprises a gamma-peptide nucleic acid. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence that arises from transcription of the non-wild type KRAS gene. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence transcribed from the non- wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non- wild type KRAS gene , wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
[00254] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a DNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K- ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene.
[00255] In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism. In some embodiments, the compound preferentially binds to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence that arises from transcription of the non- wild type KRAS gene over a mRNA sequence that arises from transcription of the wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K- ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene. In some embodiments, the compound reduces transcription of the non- wild type KRAS gene. In some embodiments, the compound reduces translation of a mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the condition is a human cancer. In some embodiments, the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma. In some embodiments, the human cancer associated with the non-wild type KRAS gene is pancreatic cancer. In some embodiments, the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II. In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
Methods of Treatment
Tumor Volume.
[00256] In some embodiments, the present disclosure provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
[00257] In some embodiments, if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm3 to about 120 mm3, and a mean tumor volume size in the test group is observed to be from about 80 mm3 to about 120 mm3; on day 5 of the study, a mean tumor volume size in the control group is determined to be from about 210 mm3 to about 250 mm3, and a mean tumor volume size in the test group is observed to be from about 140 mm3 to about 180 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 400 mm3 to about 470 mm3, and a mean tumor volume size in the test group is observed to be from about 250 mm3 to about 320 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 940 mm3, and a mean tumor volume size in the test group is observed to be from about 390 mm3 to about 550 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 1000 mm3 to about 1180 mm3, and a mean tumor volume size in the test group is observed to be from about 550 mm3 to about 770 mm3; on day 19 of the study, a mean tumor volume size in the control group is determined to be from about 1220 mm3 to about 1680 mm3, and a mean tumor volume size in the test group is observed to be from about 750 mm3 to about 1020 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 1450 mm3 to about 2000 mm3, and a mean tumor volume size in the test group is observed to be from about 900 mm3 to about 1210 mm3.
[00258] In some embodiments, if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm3 to about 120 mm3, and a mean tumor volume size in the test group is observed to be from about 80 mm3 to about 120 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 940 mm3, and a mean tumor volume size in the test group is observed to be from about 390 mm3 to about 550 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 1450 mm3 to about 2000 mm3, and a mean tumor volume size in the test group is observed to be from about 900 mm3 to about 1210 mm3.
[00259] In some embodiments, if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm3 to about 120 mm3, and a mean tumor volume size in the test group is observed to be from about 80 mm3 to about 120 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 1450 mm3 to about 2000 mm3, and a mean tumor volume size in the test group is observed to be from about 900 mm3 to about 1210 mm3.
[00260] In some embodiments, if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 10 mm3; on day 5 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 60 mm3 to about 80 mm3; on day 8 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 130 mm3 to about 150 mm3; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 360 mm3 to about 390 mm3; on day 15 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 420 mm3 to about 450 mm3; on day 19 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 540 mm3 to about 580 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 600 mm3 to about 720 mm3.
[00261] In some embodiments, if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 10 mm3; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 360 mm3 to about 390 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 600 mm3 to about 720 mm3.
[00262] In some embodiments, if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 10 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 600 mm3 to about 720 mm3.
[00263] In some embodiments, if, in a 64 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 90 mm3 to about 110 mm3, and a mean tumor volume size in the test group is observed to be from about 90 mm3 to about 110 mm3; on day 4 of the study, a mean tumor volume size in the control group is determined to be from about 100 mm3 to about 130 mm3, and a mean tumor volume size in the test group is observed to be from about 90 mm3 to about 120 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 120 mm3 to about 180 mm3, and a mean tumor volume size in the test group is observed to be from about 90 mm3 to about 130 mm3; on day 11 of the study, a mean tumor volume size in the control group is determined to be from about 170 mm3 to about 210 mm3, and a mean tumor volume size in the test group is observed to be from about 130 mm3 to about 160 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 200 mm3 to about 240 mm3, and a mean tumor volume size in the test group is observed to be from about 130 mm3 to about 190 mm3; on day 18 of the study, a mean tumor volume size in the control group is determined to be from about 200 mm3 to about 300 mm3, and a mean tumor volume size in the test group is observed to be from about 150 mm3 to about 200 mm3; on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 220 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 160 mm3 to about 230 mm3; on day 25 of the study, a mean tumor volume size in the control group is determined to be from about 310 mm3 to about 390 mm3, and a mean tumor volume size in the test group is observed to be from about 160 mm3 to about 230 mm3; on day 29 of the study, a mean tumor volume size in the control group is determined to be from about 330 mm3 to about 430 mm3, and a mean tumor volume size in the test group is observed to be from about 200 mm3 to about 290 mm3; on day 32 of the study, a mean tumor volume size in the control group is determined to be from about 370 mm3 to about 470 mm3, and a mean tumor volume size in the test group is observed to be from about 230 mm3 to about 340 mm3; on day 36 of the study, a mean tumor volume size in the control group is determined to be from about 390 mm3 to about 490 mm3, and a mean tumor volume size in the test group is observed to be from about 230 mm3 to about 350 mm3; on day 39 of the study, a mean tumor volume size in the control group is determined to be from about 400 mm3 to about 480 mm3, and a mean tumor volume size in the test group is observed to be from about 240 mm3 to about 370 mm3; on day 43 of the study, a mean tumor volume size in the control group is determined to be from about 480 mm3 to about 570 mm3, and a mean tumor volume size in the test group is observed to be from about 270 mm3 to about 400 mm3; on day 46 of the study, a mean tumor volume size in the control group is determined to be from about 500 mm3 to about 600 mm3, and a mean tumor volume size in the test group is observed to be from about 270 mm3 to about 430 mm3; and on day 50 of the study, a mean tumor volume size in the control group is determined to be from about 510 mm3 to about 610 mm3, and a mean tumor volume size in the test group is observed to be from about 310 mm3 to about 500 mm3.
[00264] In some embodiments, if, in a 64 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 90 mm3 to about 110 mm3, and a mean tumor volume size in the test group is observed to be from about 90 mm3 to about 110 mm3; on day 25 of the study, a mean tumor volume size in the control group is determined to be from about 310 mm3 to about 390 mm3, and a mean tumor volume size in the test group is observed to be from about 160 mm3 to about 230 mm3; and on day 50 of the study, a mean tumor volume size in the control group is determined to be from about 510 mm3 to about 610 mm3, and a mean tumor volume size in the test group is observed to be from about 310 mm3 to about 500 mm3. [00265] In some embodiments, if, in a 64 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 90 mm3 to about 110 mm3, and a mean tumor volume size in the test group is observed to be from about 90 mm3 to about 110 mm3; and on day 50 of the study, a mean tumor volume size in the control group is determined to be from about 510 mm3 to about 610 mm3, and a mean tumor volume size in the test group is observed to be from about 310 mm3 to about 500 mm3.
[00266] In some embodiments, if, in a 64 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 10 mm3; on day 4 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 10 mm3 to about 30 mm3; on day 8 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 30 mm3 to about 50 mm3; on day 11 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 40 mm3 to about 60 mm3; on day 15 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 50 mm3 to about 70 mm3; on day 18 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 50 mm3 to about 90 mm3; on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 70 mm3 to about 110 mm3; on day 25 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 180 mm3; on day 29 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 180 mm3; on day 32 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 180 mm3; on day 36 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 180 mm3; on day 39 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 180 mm3; on day 43 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 250 mm3; on day 46 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 300 mm3; and on day 50 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 300 mm3.
[00267] In some embodiments, if, in a 64 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 10 mm3; on day 25 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 180 mm3; and on day 50 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 300 mm3.
[00268] In some embodiments, if, in a 64 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 10 mm3; and on day 50 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 300 mm3.
[00269] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 105 mm3, and a mean tumor volume size in the test group is observed to be from about 98 mm3 to about 102 mm3; on day 5 of the study, a mean tumor volume size in the control group is determined to be from about 215 mm3 to about 260 mm3, and a mean tumor volume size in the test group is observed to be from about 175 mm3 to about 200 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 400 mm3 to about 465 mm3, and a mean tumor volume size in the test group is observed to be from about 325 mm3 to about 360 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 925 mm3, and a mean tumor volume size in the test group is observed to be from about 645 mm3 to about 705 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 1000 mm3 to about 1175 mm3, and a mean tumor volume size in the test group is observed to be from about 890 mm3 to about 960 mm3; on day 19 of the study, a mean tumor volume size in the control group is determined to be from 725 mm3 to about 1660 mm3, and a mean tumor volume size in the test group is observed to be from about 625 mm3 to about 725 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the test group is observed to be from 750 mm3 to about 865 mm3.
[00270] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 105 mm3, and a mean tumor volume size in the test group is observed to be from about 98 mm3 to about 102 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 925 mm3 and a mean tumor volume size in the test group is observed to be from about 645 mm3 to about 705 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the test group is observed to be from 750 mm3 to about 865 mm3.
[00271] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 105 mm3, and a mean tumor volume size in the test group is observed to be from about 98 mm3 to about 102 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the test group is observed to be from 750 mm3 to about 865 mm3.
[00272] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 105 mm3, and a mean tumor volume size in the test group is observed to be from about 98 mm3 to about 102 mm3; on day 5 of the study, a mean tumor volume size in the control group is determined to be from about 215 mm3 to about 260 mm3, and a mean tumor volume size in the test group is observed to be from about 175 mm3 to about 200 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 400 mm3 to about 465 mm3, and a mean tumor volume size in the test group is observed to be from about 325 mm3 to about 360 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 925 mm3 and a mean tumor volume size in the test group is observed to be from about 645 mm3 to about 705 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 1000 mm3 to about 1175 mm3, and a mean tumor volume size in the test group is observed to be from about 890 mm3 to about 960 mm3; on day 19 of the study, a mean tumor volume size in the control group is determined to be from 725 mm3 to about 1660 mm3, and a mean tumor volume size in the test group is observed to be from about 625 mm3 to about 725 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the test group is observed to be from 750 mm3 to about 865 mm3.
[00273] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 105 mm3, and a mean tumor volume size in the test group is observed to be from about 98 mm3 to about 102 mm3, on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 925 mm3 and a mean tumor volume size in the test group is observed to be from about 645 mm3 to about 705 mm3;and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the test group is observed to be from 750 mm3 to about 865 mm3.
[00274] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 105 mm3, and a mean tumor volume size in the test group is observed to be from about 98 mm3 to about 102 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the test group is observed to be from 750 mm3 to about 865 mm3.
[00275] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 80 mm3 to about 120 mm3, and a mean tumor volume size in the test group is observed to be from about 80 mm3 to about 120 mm3; on day 5 of the study, a mean tumor volume size in the control group is determined to be from about 210 mm3 to about 250 mm3, and a mean tumor volume size in the test group is observed to be from about 140 mm3 to about 180 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 400 mm3 to about 470 mm3, and a mean tumor volume size in the test group is observed to be from about 250 mm3 to about 320 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 940 mm3, and a mean tumor volume size in the test group is observed to be from about 490 mm3 to about 525 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 1000 mm3 to about 1180 mm3, and a mean tumor volume size in the test group is observed to be from about 550 mm3 to about 770 mm3; on day 19 of the study, a mean tumor volume size in the control group is determined to be from about 1750 mm3 to about 1680 mm3, and a mean tumor volume size in the test group is observed to be from about 750 mm3 to about 1020 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 1450 mm3 to about 2000 mm3, and a mean tumor volume size in the test group is observed to be from about 900 mm3 to about 1210 mm3. [00276] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 98 mm3 to about 102 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 102 mm3; on day 5 of the study, a mean tumor volume size in the first test group is determined to be from about 175 mm3 to about 200 mm3, and a mean tumor volume size in the second test group is observed to be from about 150 mm3 to about 185 mm3; on day 8 of the study, a mean tumor volume size in the first test group is determined to be from about 325 mm3 to about 360 mm3, and a mean tumor volume size in the second test group is observed to be from about 240 mm3 to about 325 mm3; on day 12 of the study, a mean tumor volume size in the first test group is determined to be from about 750 mm3 to about 925 mm3, and a mean tumor volume size in the second test group is observed to be from about 385 mm3 to about 525 mm3; on day 15 of the study, a mean tumor volume size in the first test group is determined to be from about 1000 mm3 to about 1175 mm3, and a mean tumor volume size in the second test group is observed to be from about 550 mm3 to about 760 mm3; on day 19 of the study, a mean tumor volume size in the first test group is determined to be from 725 mm3 to about 1660 mm3, and a mean tumor volume size in the second test group is observed to be from about 240 mm3 to about 525 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the second test group is observed to be from about 900 mm3 to about 1225 mm3.
[00277] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 98 mm3 to about 102 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 102 mm3; on day 12 of the study, a mean tumor volume size in the first test group is determined to be from about 750 mm3 to about 925 mm3, and a mean tumor volume size in the second test group is observed to be from about 385 mm3 to about 525 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the second test group is observed to be from about 900 mm3 to about 1225 mm3.
[00278] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 98 mm3 to about 102 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 102 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the second test group is observed to be from about 900 mm3 to about 1225 mm3.
[00279] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 3 mm3; on day 5 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 40 mm3 to about 60 mm3; on day 8 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 75 mm3 to about 105 mm3; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 105 mm3 to about 220 mm3; on day 15 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 110 mm3 to about 215 mm3; on day 19 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 935 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 215 mm3 to about 610 mm3.
[00280] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 3 mm3; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 105 mm3 to about 220 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 215 mm3 to about 610 mm3.
[00281] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 3 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 215 mm3 to about 610 mm3.
[00282] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 3 mm3; on day 5 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 15 mm3 to about 25 mm3; on day 8 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 35 mm3 to about 85 mm3; on day 12 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 365 mm3 to about 400 mm3; on day 15 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 415 mm3 to about 450 mm3; on day 19 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 485 mm3 to about 1135 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 65 mm3 to about 250 mm3.
[00283] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 3 mm3; on day 12 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 365 mm3 to about 400 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 65 mm3 to about 250 mm33.
[00284] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 3 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 65 mm3 to about 250 mm3.
[00285] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 106 mm3; on day 4 of the study, a mean tumor volume size in the control group is determined to be from about 115 mm3 to about 130 mm3, and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 108 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 150 mm3 to about 175 mm3, and a mean tumor volume size in the test group is observed to be from about 135 mm3 to about 150 mm3; on day 11 of the study, a mean tumor volume size in the control group is determined to be from about 195 mm3 to about 225 mm3, and a mean tumor volume size in the test group is observed to be from about 180 mm3 to about 195 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 218 mm3 to about 250 mm3, and a mean tumor volume size in the test group is observed to be from about 208 mm3 to about 230 mm3; on day 18 of the study, a mean tumor volume size in the control group is determined to be from about 250 mm3 to about 295 mm3, and a mean tumor volume size in the test group is observed to be from about 235 mm3 to about 252 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 255 mm3 to about 295 mm3.
[00286] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 106 mm3; on day 11 of the study, a mean tumor volume size in the control group is determined to be from about 195 mm3 to about 225 mm3, and a mean tumor volume size in the test group is observed to be from about 180 mm3 to about 195 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 255 mm3 to about 295 mm3.
[00287] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 106 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 255 mm3 to about 295 mm3.
[00288] A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 106 mm3; on day 4 of the study, a mean tumor volume size in the control group is determined to be from about 115 mm3 to about 130 mm3, and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 108 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 150 mm3 to about 175 mm3, and a mean tumor volume size in the test group is observed to be from about 135 mm3 to about 150 mm3; on day 11 of the study, a mean tumor volume size in the control group is determined to be from about 195 mm3 to about 225 mm3, and a mean tumor volume size in the test group is observed to be from about 180 mm3 to about 195 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 218 mm3 to about 250 mm3, and a mean tumor volume size in the test group is observed to be from about 208 mm3 to about 230 mm3; on day 18 of the study, a mean tumor volume size in the control group is determined to be from about 250 mm3 to about 295 mm3, and a mean tumor volume size in the test group is observed to be from about 235 mm3 to about 252 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 255 mm3 to about 295 mm3.
[00289] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 106 mm3; on day 11 of the study, a mean tumor volume size in the control group is determined to be from about 195 mm3 to about 225 mm3, and a mean tumor volume size in the test group is observed to be from about 180 mm3 to about 195 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 255 mm3 to about 295 mm3.
[00290] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 106 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 255 mm3 to about 295 mm3.
[00291] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 104 mm3; on day 4 of the study, a mean tumor volume size in the control group is determined to be from about 115 mm3 to about 130 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 115 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 150 mm3 to about 175 mm3, and a mean tumor volume size in the test group is observed to be from about 110 mm3 to about 130 mm3; on day 11 of the study, a mean tumor volume size in the control group is determined to be from about 195 mm3 to about 225 mm3, and a mean tumor volume size in the test group is observed to be from about 145 mm3 to about 162 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 218 mm3 to about 250 mm3, and a mean tumor volume size in the test group is observed to be from about 158 mm3 to about 182 mm3; on day 18 of the study, a mean tumor volume size in the control group is determined to be from about 250 mm3 to about 295 mm3, and a mean tumor volume size in the test group is observed to be from about 175 mm3 to about 205 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 190 mm3 to about 230 mm3. [00292] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 95 mm3 to about 106 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 104 mm3; on day 4 of the study, a mean tumor volume size in the first test group is determined to be from about 100 mm3 to about 108 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 115 mm3; on day 8 of the study, a mean tumor volume size in the first test group is determined to be from about 135 mm3 to about 150 mm3, and a mean tumor volume size in the second test group is observed to be from about 110 mm3 to about 130 mm3; on day 11 of the study, a mean tumor volume size in the first test group is determined to be from about 180 mm3 to about 195 mm3, and a mean tumor volume size in the second test group is observed to be from about 145 mm3 to about 162 mm3; on day 15 of the study, a mean tumor volume size in the first test group is determined to be from about 208 mm3 to about 230 mm3, and a mean tumor volume size in the second test group is observed to be from about 158 mm3 to about 182 mm3; on day 18 of the study, a mean tumor volume size in the first test group is determined to be from about 235 mm3 to about 252 mm3, and a mean tumor volume size in the second test group is observed to be from about 175 mm3 to about 205 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 255 mm3 to about 295 mm3, and a mean tumor volume size in the second test group is observed to be from about 190 mm3 to about 230 mm3.
[00293] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 95 mm3 to about 106 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 104 mm3; on day 11 of the study, a mean tumor volume size in the first test group is determined to be from about 180 mm3 to about 195 mm3, and a mean tumor volume size in the second test group is observed to be from about 145 mm3 to about 162 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 255 mm3 to about 295 mm3, and a mean tumor volume size in the second test group is observed to be from about 190 mm3 to about 230 mm3.
[00294] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 95 mm3 to about 106 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 104 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 255 mm3 to about 295 mm3, and a mean tumor volume size in the second test group is observed to be from about 190 mm3 to about 230 mm3.
[00295] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 2 mm3; on day 4 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 5 mm3 to about 7 mm3; on day 8 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 20 mm3 to about 25 mm3; on day 11 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 35 mm3 to about 33 mm3; on day 15 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 48 mm3 to about 50 mm3; on day 18 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 47 mm3 to about 60 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 60 mm3 to about 65 mm3.
[00296] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 2 mm3; on day 11 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 35 mm3 to about 33 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 60 mm3 to about 65 mm3.
[00297] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 2 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 60 mm3 to about 65 mm3.
[00298] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 2 mm3; on day 4 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 5 mm3 to about 7 mm3; on day 8 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 20 mm3 to about 25 mm3; on day 11 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 33 mm3 to about 35 mm3; on day 15 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 48 mm3 to about 50 mm3; on day 18 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 47 mm3 to about 60 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 60 mm3 to about 65 mm3.
[00299] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 2 mm3; on day 11 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 33 mm3 to about 35 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 60 mm3 to about 65 mm3.
[00300] In some embodiments, disclosed herein is a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 2 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 60 mm3 to about 65 mm3.
[00301] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 105 mm3, and a mean tumor volume size in the test group is observed to be from about 98 mm3 to about 102 mm3; on day 5 of the study, a mean tumor volume size in the control group is determined to be from about 215 mm3 to about 260 mm3, and a mean tumor volume size in the test group is observed to be from about 175 mm3 to about 200 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 400 mm3 to about 465 mm3, and a mean tumor volume size in the test group is observed to be from about 325 mm3 to about 360 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 925 mm3 and a mean tumor volume size in the test group is observed to be from about 645 mm3 to about 705 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 1000 mm3 to about 1175 mm3, and a mean tumor volume size in the test group is observed to be from about 890 mm3 to about 960 mm3; on day 19 of the study, a mean tumor volume size in the control group is determined to be from 725 mm3 to about 1660 mm3, and a mean tumor volume size in the test group is observed to be from about 625 mm3 to about 725 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the test group is observed to be from 750 mm3 to about 865 mm3.
[00302] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 105 mm3, and a mean tumor volume size in the test group is observed to be from about 98 mm3 to about 102 mm3; on day 12 of the study, a mean tumor volume size in the control group is determined to be from about 750 mm3 to about 925 mm3 and a mean tumor volume size in the test group is observed to be from about 645 mm3 to about 705 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the test group is observed to be from 750 mm3 to about 865 mm3.
[00303] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 105 mm3, and a mean tumor volume size in the test group is observed to be from about 98 mm3 to about 102 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the test group is observed to be from 750 mm3 to about 865 mm3.
[00304] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 98 mm3 to about 102 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 102 mm3; on day 5 of the study, a mean tumor volume size in the first test group is determined to be from about 175 mm3 to about 200 mm3, and a mean tumor volume size in the second test group is observed to be from about 150 mm3 to about 185 mm3; on day 8 of the study, a mean tumor volume size in the first test group is determined to be from about 325 mm3 to about 360 mm3, and a mean tumor volume size in the second test group is observed to be from about 240 mm3 to about 325 mm3; on day 12 of the study, a mean tumor volume size in the first test group is determined to be from about 750 mm3 to about 925 mm3, and a mean tumor volume size in the second test group is observed to be from about 385 mm3 to about 525 mm3; on day 15 of the study, a mean tumor volume size in the first test group is determined to be from about 1000 mm3 to about 1175 mm3, and a mean tumor volume size in the second test group is observed to be from about 550 mm3 to about 760 mm3; on day 19 of the study, a mean tumor volume size in the first test group is determined to be from 725 mm3 to about 1660 mm3, and a mean tumor volume size in the second test group is observed to be from about 240 mm3 to about 525 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the second test group is observed to be from about 900 mm3 to about 1225 mm3.
[00305] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 98 mm3 to about 102 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 102 mm3; on day 12 of the study, a mean tumor volume size in the first test group is determined to be from about 750 mm3 to about 925 mm3, and a mean tumor volume size in the second test group is observed to be from about 385 mm3 to about 525 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the second test group is observed to be from about 900 mm3 to about 1225 mm3.
[00306] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 98 mm3 to about 102 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 102 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 965 mm3 to about 1475 mm3, and a mean tumor volume size in the second test group is observed to be from about 900 mm3 to about 1225 mm3.
[00307] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 3 mm3; on day 5 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 40 mm3 to about 60 mm3; on day 8 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 75 mm3 to about 105 mm3; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 105 mm3 to about 220 mm3; on day 15 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 110 mm3 to about 215 mm3; on day 19 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 935 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 215 mm3 to about 610 mm3.
[00308] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 3 mm3; on day 12 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 105 mm3 to about 220 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 215 mm3 to about 610 mm3.
[00309] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 3 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 215 mm3 to about 610 mm3.
[00310] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 3 mm3; on day 5 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 15 mm3 to about 25 mm3; on day 8 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 35 mm3 to about 85 mm3; on day 12 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 365 mm3 to about 400 mm3; on day 15 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 415 mm3 to about 450 mm3; on day 19 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 485 mm3 to about 1135 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 65 mm3 to about 250 mm3. [00311] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 3 mm3; on day 12 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 365 mm3 to about 400 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 65 mm3 to about 250 mm3.
[00312] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 3 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 65 mm3 to about 250 mm3.
[00313] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 106 mm3; on day 4 of the study, a mean tumor volume size in the control group is determined to be from about 115 mm3 to about 130 mm3, and a mean tumor volume size in the test group is observed to be from about 100 mm3 to about 108 mm3; on day 8 of the study, a mean tumor volume size in the control group is determined to be from about 150 mm3 to about 175 mm3, and a mean tumor volume size in the test group is observed to be from about 135 mm3 to about 150 mm3; on day 11 of the study, a mean tumor volume size in the control group is determined to be from about 195 mm3 to about 225 mm3, and a mean tumor volume size in the test group is observed to be from about 180 mm3 to about 195 mm3; on day 15 of the study, a mean tumor volume size in the control group is determined to be from about 218 mm3 to about 250 mm3, and a mean tumor volume size in the test group is observed to be from about 208 mm3 to about 230 mm3; on day 18 of the study, a mean tumor volume size in the control group is determined to be from about 250 mm3 to about 295 mm3, and a mean tumor volume size in the test group is observed to be from about 235 mm3 to about 252 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 255 mm3 to about 295 mm3.
[00314] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 106 mm3; on day 11 of the study, a mean tumor volume size in the control group is determined to be from about 195 mm3 to about 225 mm3, and a mean tumor volume size in the test group is observed to be from about 180 mm3 to about 195 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 255 mm3 to about 295 mm3.
[00315] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the control group is determined to be from about 95 mm3 to about 108 mm3, and a mean tumor volume size in the test group is observed to be from about 95 mm3 to about 106 mm3; and on day 22 of the study, a mean tumor volume size in the control group is determined to be from about 280 mm3 to about 320 mm3, and a mean tumor volume size in the test group is observed to be from about 255 mm3 to about 295 mm3.
[00316] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 95 mm3 to about 106 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 104 mm3; on day 4 of the study, a mean tumor volume size in the first test group is determined to be from about 100 mm3 to about 108 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 115 mm3; on day 8 of the study, a mean tumor volume size in the first test group is determined to be from about 135 mm3 to about 150 mm3, and a mean tumor volume size in the second test group is observed to be from about 110 mm3 to about 130 mm3; on day 11 of the study, a mean tumor volume size in the first test group is determined to be from about 180 mm3 to about 195 mm3, and a mean tumor volume size in the second test group is observed to be from about 145 mm3 to about 162 mm3; on day 15 of the study, a mean tumor volume size in the first test group is determined to be from about 208 mm3 to about 230 mm3, and a mean tumor volume size in the second test group is observed to be from about 158 mm3 to about 182 mm3; on day 18 of the study, a mean tumor volume size in the first test group is determined to be from about 235 mm3 to about 252 mm3, and a mean tumor volume size in the second test group is observed to be from about 175 mm3 to about 205 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 255 mm3 to about 295 mm3, and a mean tumor volume size in the second test group is observed to be from about 190 mm3 to about 230 mm3.
[00317] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 95 mm3 to about 106 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 104 mm3; on day 11 of the study, a mean tumor volume size in the first test group is determined to be from about 180 mm3 to about 195 mm3, and a mean tumor volume size in the second test group is observed to be from about 145 mm3 to about 162 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 255 mm3 to about 295 mm3, and a mean tumor volume size in the second test group is observed to be from about 190 mm3 to about 230 mm3.
[00318] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a mean tumor volume size in the first test group is determined to be from about 95 mm3 to about 106 mm3, and a mean tumor volume size in the second test group is observed to be from about 95 mm3 to about 104 mm3; and on day 22 of the study, a mean tumor volume size in the first test group is determined to be from about 255 mm3 to about 295 mm3, and a mean tumor volume size in the second test group is observed to be from about 190 mm3 to about 230 mm3.
[00319] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 2 mm3; on day 4 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 5 mm3 to about 7 mm3; on day 8 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 20 mm3 to about 25 mm3; on day 11 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 35 mm3 to about 33 mm3; on day 15 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 48 mm3 to about 50 mm3; on day 18 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 47 mm3 to about 60 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 60 mm3 to about 65 mm3.
[00320] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 2 mm3; on day 11 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 35 mm3 to about 33 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 60 mm3 to about 65 mm3.
[00321] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the wild type KRAS gene is subcutaneously implanted into each of six mice in a control group, and each mouse in the control group receives intra-tumoral injection of a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a test group, and each mouse in the test group receives intra-tumoral injection of 0.1 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 0 mm3 to about 2 mm33; and on day 22 of the study, a difference between a mean tumor volume size in the control group and a mean tumor volume size in the test group is observed to be from about 60 mm3 to about 65 mm3.
[00322] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 2 mm3; on day 4 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 5 mm3 to about 7 mm3; on day 8 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 20 mm3 to about 25 mm3; on day 11 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 33 mm3 to about 35 mm3; on day 15 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 48 mm3 to about 50 mm3; on day 18 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 47 mm3 to about 60 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 60 mm3 to about 65 mm3.
[00323] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 2 mm3; on day 11 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 33 mm3 to about 35 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 60 mm3 to about 65 mm3.
[00324] In some embodiments, disclosed herein is a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue, wherein if, in a 22 day study: a) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a first test group, and each mouse in the first test group receives intra-tumoral injection of 0.1 mg/kg of the compound in a vehicle on days 1, 7, and 14 of the study; and b) a tumor of a human cancer associated with the non-wild type KRAS gene is subcutaneously implanted into each of six mice in a second test group, and each mouse in the second test group receives intra-tumoral injection of 0.3 mg/kg of the compound in the vehicle on days 1, 7, and 14 of the study, then: on day 1 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 0 mm3 to about 2 mm3; and on day 22 of the study, a difference between a mean tumor volume size in the first test group and a mean tumor volume size in the second test group is observed to be from about 60 mm3 to about 65 mm3.
[00325] In some embodiments, the compound is a DNA binding agent. [00326] In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
[00327] In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the KRAS gene of the subject, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the KRAS gene of the subject.
[00328] In some embodiments, the peptide nucleic acid sequence is complementary to the non- wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene.
[00329] In some embodiments, the peptide nucleic acid sequence is complementary to the non- wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism.
[00330] In some embodiments, the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the gene of the subject.
[00331] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a DNA sequence in the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to the mRNA sequence of the subject. [00332] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject. In some embodiments, the compound reduces expression of the non- wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
[00333] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject, wherein the mRNA sequence of the subject transcribed from non- wild type KRAS gene of the subject comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject. In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T).
[00334] In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
[00335] In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non- wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non- wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the gene of the subject.
[00336] In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to the non-wild type gene over the wild-type gene. In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism.
[00337] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence transcribed from the non-wild type gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
[00338] In some embodiments, the compound reduces transcription of the non-wild type KRAS gene in the subject. In some embodiments, the compound reduces translation of the mRNA sequence transcribed from the non-wild type gene in the subject.
[00339] In some embodiments, the condition is cancer. In some embodiments, the condition is cancer associated with a mutation in a KRAS gene In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma.
[00340] In some embodiments, the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma. In some embodiments, the human cancer associated with the non- wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II.
[00341] In some embodiments, the therapeutically-effective amount is 0.01 mg/kg. In some embodiments, the therapeutically-effective amount is 0.05 mg/kg. In some embodiments, the therapeutically-effective amount is 0.1 mg/kg. In some embodiments, the therapeutically- effective amount is 0.2 mg/kg. In some embodiments, the therapeutically-effective amount is 0.3 mg/kg. In some embodiments, the therapeutically-effective amount is 0.4 mg/kg. In some embodiments, the therapeutically-effective amount is 0.5 mg/kg.
[00342] In some embodiments, the administering is oral. In some embodiments, the administering is intravenous.
[00343] In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
[00344] In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A).
[00345] In some embodiments, the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non- wild type K-ras protein is K-ras G12C.
[00346] In some embodiments, the compound has the formula:
Figure imgf000180_0001
whereineachBisindependentlythenucleobaseofthepluralityofnucleobase-bearingsidechains,whereinthepeptidenucleicacidsequencehasanucleobasesequencethatis:guanine,cytosine,cytosine,thymine,adenine,cytosine,guanine,cytosine,cytosine,adenine,thymine,cytosine,adenine,guanine,cytosine,thymine,cytosine,cytosine,adenine,adenine,orapharmaceuticallyacceptablesaltorionizedformthereof[00347]Insomeembodiments,thecompoundhastheformula:
Figure imgf000181_0001
whereineachofB1andB2isindependentlythenucleobaseofthepluralityofnucleobase-bearingsidechains,whereinthepeptidenucleicacidsequencehasanucleobasesequencethatis:thymine,guanine,cytosine,cytosine,thymine,adenine,cytosine,guanine,cytosine,cytosine,adenine,adenine,cytosine,adenine,guanine,cytosine,thymine,cytosine,cytosine,adenine,orapharmaceuticallyacceptablesaltorionizedformthereof OncogenicSignaling. [00348]Insomeembodiments,thepresentdisclosureprovidesamethodoftreatingaconditionassociatedwithnon-wildtypeKRAS,themethodcomprisingadministeringtoasubjectinneedthereofatherapeutically-effectiveamountofacompound,whereinthecompoundcomprisesapeptidenucleicacidsequence,whereinthepeptidenucleicacidsequencebindstoanucleicacidsequenceassociatedwithanon-wildtypeKRASgene,whereinif,inastudy: a) i) atestSCIDmousethatis5-9weeksoldisinoculatedwithaboutonemillionHPAF- IIcellsbysubcutaneousinjection,andatumorhavingavolumeofabout100mm3 formsinthetestSCIDmouse; ii) afterthetumorforms,thetestSCIDmouseisdosedintratumorallyonceperweekfor threeconsecutiveweekswiththecompoundinavehicleatoneof0.3μM,1μM ,3 μM,10μM,and30μM; iii)afterthethreeconsecutiveweeks,thetestSCIDmouseismonitoreduntilthetumor thatformsinthetestSCIDmousehasavolumeofabout1,500mm3; iv) afterthetumorthatformsinthetestSCIDmousereachesavolumeofabout1,500 mm3,asampleofthetumorisharvested,frozen,andlasermicrodissectedwhile frozentoprovideasectionofthetumorthatformsinthetestSCIDmouse;and v) thesectionofthetumorthatformsinthetestSCIDmouseisanalyzedbyreverse phaseproteinarraytoquantifyanamountofphospho-MEKinthesectionofthe tumor that forms in the test SCID mouse; and b) i) a control SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF-II cells by subcutaneous injection, and a tumor having a volume of about 100 mm3 forms in the control SCID mouse; ii) after the tumor forms, the control SCID mouse is dosed intratumorally once per week for three consecutive weeks with the vehicle; iii) after the three consecutive weeks, the control SCID mouse is monitored until the tumor that forms in the control SCID mouse has a volume of about 1,500 mm3; iv) after the tumor that forms in the control SCID mouse reaches a volume of about 1,500 mm3, a sample of the tumor is harvested, frozen, and laser microdissected while frozen to provide a section of the tumor that forms in the control SCID mouse; and v) the section of the tumor that forms in the control SCID mouse is analyzed by reverse phase protein array to quantify an amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse, then the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be at most about 70% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
[00349] In some embodiments, the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be at most about 55% of the amount of phospho- MEK in the section of the tumor that forms in the control SCID mouse.
[00350] In some embodiments, the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be about 40% to about 60% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
[00351] In some embodiments, the amount of phospho-MEK in the section of the tumor that forms in the test SCID mouse is determined to be about 40% to about 50% of the amount of phospho-MEK in the section of the tumor that forms in the control SCID mouse.
[00352] In some embodiments, the peptide nucleic acid sequence binds to a mRNA sequence transcribed from the non- wild type KRAS gene.
[00353] In some embodiments, the condition is cancer. In some embodiments, the condition is cancer associated with a mutation in a KRAS gene. In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma.
[00354] In some embodiments, the present disclosure provides a method of treating a condition associated with non-wild type KRAS, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid sequence associated with a non-wild type KRAS gene, wherein if, in a study: a) i) a test SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF- II cells by subcutaneous injection, and a tumor having a volume of about 100 mm3 forms in the test SCID mouse; ii) after the tumor forms, the test SCID mouse is dosed intratumorally once per week for three consecutive weeks with the compound in a vehicle at one of 0.3 μM, 1 μM, 3 μM, 10 μM, and 30 μM; iii) after the three consecutive weeks, the test SCID mouse is monitored until the tumor that forms in the test SCID mouse has a volume of about 1,500 mm3; iv) after the tumor that forms in the test SCID mouse reaches a volume of about 1,500 mm3, a sample of the tumor is harvested, frozen, and laser microdissected while frozen to provide a section of the tumor that forms in the test SCID mouse; and v) the section of the tumor that forms in the test SCID mouse is analyzed by reverse phase protein array to quantify an amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse; and b) i) a control SCID mouse that is 5-9 weeks old is inoculated with about one million HPAF-II cells by subcutaneous injection, and a tumor having a volume of about 100 mm3 forms in the control SCID mouse; ii) after the tumor forms, the control SCID mouse is dosed intratumorally once per week for three consecutive weeks with the vehicle; iii) after the three consecutive weeks, the control SCID mouse is monitored until the tumor that forms in the control SCID mouse has a volume of about 1,500 mm3; iv) after the tumor that forms in the control SCID mouse reaches a volume of about 1,500 mm3, a sample of the tumor is harvested, frozen, and laser microdissected while frozen to provide a section of the tumor that forms in the control SCID mouse; and v) the section of the tumor that forms in the control SCID mouse is analyzed by reverse phase protein array to quantify an amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse, then the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 50% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
[00355] In some embodiments, the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 40% of the amount of phospho- CREB in the section of the tumor that forms in the control SCID mouse.
[00356] In some embodiments, the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be at most about 30% of the amount of phospho- CREB in the section of the tumor that forms in the control SCID mouse.
[00357] In some embodiments, the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be from about 10% to about 30% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
[00358] In some embodiments, the amount of phospho-CREB in the section of the tumor that forms in the test SCID mouse is determined to be from about 15% to about 25% of the amount of phospho-CREB in the section of the tumor that forms in the control SCID mouse.
[00359] In some embodiments, the peptide nucleic acid sequence binds to a mRNA sequence transcribed from the non- wild type KRAS gene.
[00360] In some embodiments, the condition is cancer. In some embodiments, the condition is cancer associated with a mutation in a KRAS gene. In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma.
[00361] In some embodiments, the compound has the formula:
Figure imgf000184_0001
wherein each B is independently a nucleobase, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, thymine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, adenine, or a pharmaceutically acceptable salt, ionized form, or tautomer thereof.
[00362] In some embodiments, the compound has the formula:
Figure imgf000185_0001
wherein each of B1 and B2 is independently a nucleobase, wherein the peptide nucleic acid sequence has a nucleobase sequence that is: thymine, guanine, cytosine, cytosine, thymine, adenine, cytosine, guanine, cytosine, cytosine, adenine, adenine, cytosine, adenine, guanine, cytosine, thymine, cytosine, cytosine, adenine, or a pharmaceutically acceptable salt, ionized form, or tautomer thereof.
Modes of Administration
[00363] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered to a subject in various forms and by various suitable routes of administration.
[00364] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered in a systemic manner. [00365] In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered parenterally. Parenteral administration can be, for example, by bolus injection or by gradual infusion or perfusion over time. Administration can also be by surgical deposition of a bolus or positioning of a medical device.
[00366] In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered orally. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by an intravenous, intratumoral, subcutaneous, intramuscular, intracerebral, intracerebroventricular, intra-articular, intraperitoneal, intracranial, intrathecal, intranasal, buccal, sublingual, oral, or rectal administration route. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intravenous administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by subcutaneous administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intramuscular administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intracerebroventricular administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by oral administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intrathecal administration. [00367] Any aforementioned route of administration can be combined with another route of administration. For example, a compound provided herein can be delivered by a first route of administration, and one or more subsequent maintenance doses of the compound can be delivered by the same or a different route of administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intramuscular administration, and one or more subsequent maintenance doses of the compound or the composition comprising the compound are delivered by subcutaneous administration or intravenous administration.
[00368] Non-limiting examples of suitable modes and routes of administration include oral, topical, parenteral, intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, intramuscular infusion, intradermal injection, intradermal infusion, intraperitoneal injection, intraperitoneal infusion, intracerebral injection, intracerebral infusion, subarachnoid injection, subarachnoid infusion, intraocular injection, intraspinal injection, intrastemal injection, ophthalmic administration, endothelial administration, local administration, intranasal administration, intrapulmonary administration, rectal administration, intraarterial administration, intrathecal administration, inhalation, intralesional administration, intradermal administration, transdermal administration (e.g., via emulsion/liposome-mediated methods of delivery with the compound optionally packaged into liposomes), epidural administration, absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa), intracapsular administration, subcapsular administration, intracardiac administration, transtracheal administration, subcuticular administration, subarachnoid administration, subcapsular administration, intraspinal administration, and intrastemal administration.
[00369] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered via a non-invasive method. Examples of non-invasive modes of administering can include using a needleless injection device, and topical administration, e.g., eye drops. Multiple administration routes can be employed for efficient delivery.
[00370] Depending on the intended mode of administration, the compositions can be in the form of solid, semi solid or liquid dosage forms, such as, e g., tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, e.g., in unit dosage form suitable for single administration of a precise dosage. The composition can be formulated into any suitable dosage form for administration, e.g., aqueous dispersions, liquids, gels, syrups, elixirs, slurries, and suspensions, for administration to a subject or a patient.
[00371] Solid compositions include, e.g., powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, e.g., solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, e.g., gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. [00372] In some embodiments, the composition is formulated into solutions (e.g., for IV administration). In some cases, the pharmaceutical composition is formulated as an infusion. In some cases, the pharmaceutical composition is formulated as an injection.
[00373] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release.
[00374] A composition comprising a compound provided herein can be, e.g., an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements, or has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix -based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses. [00375] In some embodiments, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, e.g., for about 4, about 8, about 12, about 16, or about 24 hours. A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, e.g., the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.
[00376] A pharmaceutical composition disclosed herein can be targeted to any suitable tissue or cell type. Modes, routes, and compositions provided herein can be suitable to target a compound provided herein to a particular tissue, or a subset of tissues. Non-limiting examples of tissues that can be targeted include kidney (e.g., kidney cortex), joints, cartilage, liver, salivary glands, bone (e.g., bone surface), skin, lung, muscle, pancreas, hair follicles, large intestine mucosa, aortic wall, small intestine mucosa, adrenal gland, stomach mucosa, spleen, bone marrow, lymph nodes, thymus, brain, cerebellum, olfactory bulb, thalamus, caudate putamen, cerebral cortex, substantia nigra, lateral ventricle, choroid plexus, and combinations thereof.
[00377] Compounds can be introduced into cells by, e.g., transfection, electroporation, fusion, liposomes, colloidal polymeric particles, and viral and non-viral vectors. Compounds provided herein can also be delivered using, e.g., methods involving liposome-mediated uptake, lipid conjugates, polylysine-mediated uptake, nanoparticle-mediated uptake, and receptor-mediated endocytosis, as well as additional non-endocytic modes of delivery, such as microinjection, permeabilization (e.g., streptolysin-O permeabilization, anionic peptide permeabilization), electroporation, and various non-invasive non-endocytic methods of delivery.
[00378] The method of delivery can depend at least on the cells to be treated and the location of the cells. For instance, localization can be achieved by liposomes with specific markers on the surface to direct the liposome, direct injection into tissue containing target cells, specific receptor mediated uptake, or viral vectors.
[00379] In some embodiments, a compound disclosed herein is delivered via an implantable device, e.g., synthetic implant design.
[00380] Compounds provided herein can be administered in any physiologically and/or pharmaceutically acceptable vehicle or carrier. Non-limiting examples of pharmaceutically acceptable carriers include saline, phosphate buffered saline (PBS), water, aqueous ethanol, emulsions, such as oil/water emulsions or triglyceride emulsions, tablets, and capsules. The choice of suitable physiologically acceptable carrier can vary depending upon the chosen mode of administration. A pharmaceutically acceptable carrier can include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
[00381] Further provided are prodrugs of a compound provided herein. Prodrugs can be covalently bonded carriers that release a compound in vivo when administered to a subject. Prodrugs can be prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, to yield the biologically active compound. Non-limiting examples of prodrugs include acetate, formate, and benzoate derivatives of alcohol and amine functional groups of compounds provided herein. Further, in the case of a carboxylic acid functional group ( — COOH), esters can be used, such as methyl esters and ethyl esters. [00382] In some embodiments, liposomes can be used to facilitate uptake of a compound provided herein into cells. Hydrogels can also be used as vehicles for compound administration. Alternatively, a compound provided herein can be administered in microspheres or microparticles. Alternatively, the use of gas-filled microbubbles complexed with a compound provided herein can enhance delivery to target tissues. Sustained release compositions can also be used, including, e.g., semipermeable polymeric matrices in the form of shaped articles such as films or microcapsules.
[00383] In some embodiments, a compound provided herein is administered to a mammalian subject, e.g., human or domestic animal that is exhibiting the symptoms of a polynucleotide repeat expansion disorder. Compounds provided herein can selectively reduce expression of a mutant protein in the subject. In some embodiments, the subject is a human subject, e.g., a patient diagnosed as having a polynucleotide repeat disease. In some embodiments, a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered orally. In some embodiments, a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered intravenously.
[00384] In some embodiments, the subject is a vertebrate. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a subject is a non-human subject. In some embodiments, a subject is a veterinary subject.
[00385] In some embodiments, the patient is a vertebrate. In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the patient is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a patient is a non-human patient. In some embodiments, a patient is a veterinary patient.
[00386] In some embodiments, a patient and a subject are the same species. In some embodiments, a subject and a patient are human.
[00387] In some embodiments, a patient and a subject are different species. In some embodiments, a subject is human and a patient is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig. In some embodiments, a patient is human and a subject is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig.
[00388] An effective in vivo treatment regimen using the compounds provided herein can vary according to the duration, dose, frequency, and route of administration, as well as the condition of the subject under treatment (i.e., prophylactic administration versus administration in response to localized or systemic infection). Accordingly, such in vivo therapy can require monitoring by tests appropriate to the particular type of disorder under treatment, and corresponding adjustments in the dose or treatment regimen, in order to achieve an optimal therapeutic outcome.
[00389] The efficacy of an in vivo administered compound provided herein can be determined from biological samples (e.g., tissue, blood, urine) taken from a subject prior to, during, and subsequent to administration of the compound. Assays of such samples can include (1) monitoring the presence or absence of heteroduplex formation with target and non-target sequences, e.g., by an electrophoretic gel mobility assay; and (2) monitoring the amount of a mutant mRNA or protein in relation to a reference wild-type mRNA or protein as determined by standard techniques such as RT-PCR, Northern blotting, ELISA, or Western blotting.
[00390] In some embodiments, the compound provided herein is actively taken up by mammalian cells. In further embodiments, the compound provided herein can be conjugated to a transport moiety (e.g., transport peptide) as described herein to facilitate such uptake.
[00391] Compounds provided herein can be administered to subjects to treat (prophylactically or therapeutically) disorders associated with aberrant expression of a mRNA or protein produced from a mutant polynucleotide repeat containing allele. In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual's genotype and the individual's response to a foreign compound or drug) can be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a therapeutic agent as well as tailoring the dosage and/or therapeutic regimen of treatment with the therapeutic agent.
K-ras Expression.
[00392] In some embodiments, the present disclosure provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the condition is associated with a non-wild type gene in the subject, wherein the non- wild type gene differs from a corresponding wild type gene in a single nucleotide polymorphism, wherein the single nucleotide polymorphism in the subject encodes for expression of a mutant protein that contributes to the condition, wherein the compound reduces expression of the mutant protein in the subject.
[00393] In some embodiments, the compound is a nucleic acid binding agent. In some embodiments, the compound is a DNA binding agent. In some embodiments, the compound is a RNA binding agent. In some embodiments, the compound is a mRNA binding agent. In some embodiments, the compound comprises a peptide nucleic acid sequence. In some embodiments, the compound comprises a gamma-peptide nucleic acid sequence.
[00394] In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with the non-wild type gene. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence that arises from transcription of the non-wild type gene. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with the non-wild type gene, wherein one nucleobase binds to the single nucleotide polymorphism. In some embodiments, the compound comprises a plurality of nucleobase- bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence that arises from transcription of the non-wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that is complementary to the non-wild type gene. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that is complementary to a mRNA sequence that arises from transcription of the non-wild type gene. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that is complementary to the non-wild type gene, wherein one nucleobase binds to the single nucleotide polymorphism. In some embodiments, the compound comprises a plurality of nucleobase- bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that is complementary to a mRNA sequence that arises from transcription of the non-wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject, and wherein one of the nucleobases from the sequence that is complementary to the mRNA sequence that arises from transcription of the non-wild type gene binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject.
[00395] In some embodiments, the compound reduces expression of the mutant protein by binding to a nucleic acid of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a DNA sequence in the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a RNA sequence of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a mRNA sequence of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to the non-wild type gene of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a mRNA sequence of the subject that arises from transcription of the non-wild type gene of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to the single nucleotide polymorphism of the non-wild type gene of the subject. In some embodiments, the compound reduces expression of the mutant protein by binding to a mRNA sequence of the subject that arises from transcription of the non-wild type gene of the subject, wherein the mRNA sequence of the subject that arises from transcription of the non-wild type gene of the subject comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subj ect.
[00396] In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T).
[00397] In some embodiments, the compound preferentially binds to the non-wild type gene over the wild type gene. In some embodiments, the compound preferentially binds to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene. In some embodiments, the compound preferentially binds to the non-wild type gene over the wild-type gene, and wherein the compound binds the non-wild-type gene at the single nucleotide polymorphism. In some embodiments, the compound preferentially binds to a mRNA sequence that arises from transcription of the non- wild type gene over a mRNA sequence that arises from transcription of the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject. In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to the non-wild type gene over the wild-type gene. In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene. In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to the non-wild type gene over the wild-type gene, and wherein the compound binds the non-wild-type gene at the single nucleotide polymorphism. In some embodiments, the compound reduces expression of the mutant protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type gene over a mRNA sequence that arises from transcription of the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject.
[00398] In some embodiments, the compound reduces transcription of the non-wild type gene in the subject. In some embodiments, the compound reduces translation of the non-wild type gene in the subject.
[00399] In some embodiments, the condition is cancer. In some embodiments, the condition is a human cancer. In some embodiments, the condition is cancer associated with a mutation in a KRAS gene. In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma. In some embodiments, the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma. In some embodiments, the condition is a human cancer associated with a non-wild type KRAS gene that is HPAFII. In some embodiments, the condition is a human cancer associated with a non-wild type KRAS gene that is CAPAN-II. In some embodiments, the condition is the human cancer associated with a non- wild type KRAS gene is pancreatic cancer. In some embodiments, the human cancer associated with a non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with a non-wild type KRAS gene is CAPAN-II.
[00400] In some embodiments, the therapeutically-effective amount is about 0.01 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.05 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.1 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.2 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.3 mg/kg. In some embodiments, the therapeutically- effective amount is about 0.4 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.5 mg/kg.
[00401] In some embodiments, the administering is oral. In some embodiments, the administering is intravenous. In some embodiments, the administering is subcutaneous.
[00402] In some embodiments, the wild type gene is KRAS. In some embodiments, the non- wild type gene is mutant KRAS. In some embodiments, the wild type gene is KRAS, the non- wild type gene is mutant KRAS, and the single nucleotide polymorphism results in a G12D mutation in the mutant protein. In some embodiments, the wild type gene is KRAS, the non-wild type gene is mutant KRAS, and the single nucleotide polymorphism results in a G12V mutation in the mutant protein. In some embodiments, the wild type gene is KRAS, the non-wild type gene is mutant KRAS, and the single nucleotide polymorphism results in a G12C mutation in the mutant protein. In some embodiments, the mutant protein is K-ras G12D. In some embodiments, the mutant protein is K-ras G12V. In some embodiments, the mutant protein is K- ras G12C.
[00403] In some embodiments, the present disclosure provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a mRNA sequence transcribed from a non- wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
[00404] In some embodiments if, in a study: a) a first assay is performed to determine a mean in vitro expression of the wild type K- ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about 1 mM of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K-ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the wild type K-ras protein in the sample by quantifying the luminescence; b) a second assay is performed to determine a mean in vitro expression of the non-wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the non-wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about 1 mM of the compound to produce an amount of the non-wild type K-ras protein, wherein the amount of the non-wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the non-wild type K-ras protein, contacting the non-wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the non-wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the non-wild type K-ras protein in the sample by quantifying the luminescence; c) a first control experiment is performed to determine a mean control in vitro expression of the wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in absence of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K-ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the wild type K-ras protein in the sample by quantifying the luminescence; and d) a second control experiment is performed to determine a mean control in vitro expression of the non-wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the non-wild type K-ras protein is exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in absence of the compound to produce an amount of the non-wild type K-ras protein, wherein the amount of the non-wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the non-wild type K-ras protein, contacting the non-wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the non-wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the non-wild type K-ras protein in the sample by quantifying the luminescence, then: i) the mean in vitro expression of the wild type K-ras protein is determined to be within 5% of the mean control in vitro expression of the wild type K-ras protein; ii) the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 10% lesser than is the mean control in vitro expression of the non-wild type K-ras protein; and iii) the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 10% lesser than is the mean in vitro expression of the wild type K-ras protein.
[00405] In some embodiments, the mean in vitro expression of the wild type K-ras protein is determined to be within 1% of the mean control in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean control in vitro expression of the non-wild type K-ras protein.
[00406] In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean in vitro expression of the wild type K-ras protein. [00407] In some embodiments, the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non- wild type K-ras protein is K-ras G12C. In some embodiments, the compound is a DNA binding agent. In some embodiments, the compound comprises a gamma-peptide nucleic acid. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism. In some embodiments, the peptide nucleic acid sequence is complementary to the mRNA sequence transcribed from the non- wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
[00408] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a DNA sequence in the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a mRNA sequence of the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the mRNA sequence transcribed from the non-wild type KRAS gene of the subject, wherein the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject. In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non- wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the nonwild-type KRAS gene at the single nucleotide polymorphism. In some embodiments, the compound preferentially binds to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type KRAS gene over a mRNA sequence that arises from transcription of the wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the nonwild-type KRAS gene at the single nucleotide polymorphism. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to the mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence that arises from transcription of the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type gene of the subject. In some embodiments, the compound reduces transcription of the non-wild type KRAS gene in the subject. In some embodiments, the compound reduces translation of the mRNA sequence transcribed from the non-wild type KRAS gene in the subject.
[00409] In some embodiments, the condition is cancer. In some embodiments, the condition is a human cancer. In some embodiments, the condition is cancer associated with a mutation in the non-wild type KRAS gene. In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma. In some embodiments, the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma. In some embodiments, the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II. In some embodiments, the human cancer associated with the non-wild type KRAS gene is pancreatic cancer. In some embodiments, the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non- wild type KRAS gene is CAPAN-II. In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non- wild type K-ras protein. In some embodiments, the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non-wild type K-ras protein is K-ras G12C.
[00410] In some embodiments, the therapeutically-effective amount is about 0.01 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.05 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.1 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.2 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.3 mg/kg. In some embodiments, the therapeutically- effective amount is about 0.4 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.5 mg/kg.
[00411] In some embodiments, the administering is oral. In some embodiments, the administering is intravenous. In some embodiments, the administering is subcutaneous.
[00412] In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein. [00413] In some embodiments, the present disclosure provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a non-wild type KRAS gene, wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism, wherein the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
[00414] In some embodiments, if, in a study: a) a first assay is performed to determine a mean in vitro expression of the wild type K- ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about 1 mM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about 1 mM of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K- ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the wild type K-ras protein in the sample by quantifying the luminescence; b) a second assay is performed to determine a mean in vitro expression of the non-wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the non-wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about 1 mM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in presence of the compound at a concentration of about 1 mM of the compound to produce an amount of the non-wild type K-ras protein, wherein the amount of the non-wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the non-wild type K-ras protein, contacting the non-wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the non-wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the non-wild type K-ras protein in the sample by quantifying the luminescence; c) a first control experiment is performed to determine a mean control in vitro expression of the wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about 1 mM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in absence of the compound to produce an amount of the wild type K-ras protein, wherein the amount of the wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the wild type K-ras protein, contacting the wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the wild type K-ras protein in the sample by quantifying the luminescence; and d) a second control experiment is performed to determine a mean control in vitro expression of the non-wild type K-ras protein in a group of samples, wherein in each sample of the group, 100 ng of DNA encoding for the non-wild type K-ras protein is incubated at about 37 °C for about 30 minutes in presence of the compound at a concentration of about 1 iiM of the compound, then exposed to cell-free in vitro transcription and translation conditions at about 37 °C for about 1 hour in absence of the compound to produce an amount of the non-wild type K- ras protein, wherein the amount of the non-wild type K-ras protein in each sample is quantified by electrophoresis of the sample by SDS-PAGE to isolate the non-wild type K-ras protein, contacting the non-wild type K-ras protein with a conjugate of K-Ras Recombinant Rabbit Monoclonal Antibody conjugated to horseradish peroxidase, then contacting the non-wild type K-ras protein with a chemiluminescent substrate of horseradish peroxidase to generate luminescence, then quantifying the amount of the non-wild type K-ras protein in the sample by quantifying the luminescence, then: i) the mean in vitro expression of the wild type K-ras protein is determined to be within 30% of the mean control in vitro expression of the wild type K-ras protein; ii) the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 10% lesser than is the mean control in vitro expression of the non-wild type K-ras protein; and iii) the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 10% lesser than is the mean in vitro expression of the wild type K-ras protein.
[00415] In some embodiments, the mean in vitro expression of the wild type K-ras protein is determined to be within 5% of the mean control in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean control in vitro expression of the non- wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean control in vitro expression of the nonwild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean control in vitro expression of the non-wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 65% lesser than to about 95% lesser than the mean control in vitro expression of the non-wild type K-ras protein.
[00416] In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 20% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 30% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 40% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 50% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 60% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 70% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 80% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be at least 90% lesser than is the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the non-wild type K-ras protein is determined to be about 30% lesser than to about 50% lesser than the mean in vitro expression of the wild type K-ras protein. In some embodiments, the mean in vitro expression of the nonwild type K-ras protein is determined to be about 65% lesser than to about 95% lesser than the mean in vitro expression of the wild type K-ras protein. In some embodiments, the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K- ras G12V. In some embodiments, the non-wild type K-ras protein is K-ras G12C.
[00417] In some embodiments, the compound is a nucleic acid binding agent. In some embodiments, the compound is a DNA binding agent. In some embodiments, the compound is a RNA binding agent. In some embodiments, the compound is a mRNA binding agent. In some embodiments, the compound comprises a gamma-peptide nucleic acid. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence that arises from transcription of the non-wild type KRAS gene. In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein one nucleobase binds to the single nucleotide polymorphism.
In some embodiments, the compound comprises a plurality of nucleobase-bearing side chains, wherein each nucleobase-bearing side chain independently comprises a nucleobase, wherein the nucleobases form a sequence that hybridizes with a mRNA sequence transcribed from the non- wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non- wild type KRAS gene of the subject, wherein the nucleobase of one of the nucleobase-bearing side chains binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene. In some embodiments, the peptide nucleic acid sequence is complementary to the non-wild type KRAS gene, wherein one nucleobase of the peptide nucleic acid sequence binds to the single nucleotide polymorphism. In some embodiments, the peptide nucleic acid sequence is complementary to a mRNA sequence transcribed from the non-wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein one of the nucleobases from the peptide nucleic acid sequence binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
[00418] In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a nucleic acid of the subject. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a DNA sequence in the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a RNA sequence of the subj ect. In some embodiments, the compound reduces expression of the non -wild type K-ras protein by binding to a mRNA sequence of the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a mRNA sequence of the subject transcribed from the non- wild type KRAS gene of the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by binding to a mRNA sequence transcribed from the non-wild type KRAS gene of the subject, wherein the mRNA sequence of the subject transcribed from the non-wild type KRAS gene of the subject comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
[00419] In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>T). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.35G>A). In some embodiments, the single nucleotide polymorphism of the non-wild type KRAS gene is (c.34G>T). In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild type KRAS gene. In some embodiments, the compound preferentially binds to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene. In some embodiments, the compound preferentially binds to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism. In some embodiments, the compound preferentially binds to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type KRAS gene, wherein the mRNA sequence transcribed from the non-wild type KRAS gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject. In some embodiments, the compound reduces expression of the non- wild type K-ras protein by preferentially binding to the non-wild type KRAS gene over the wild- type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence that arises from transcription of the non-wild type KRAS gene over a mRNA sequence that arises from transcription of the wild type KRAS gene. In some embodiments, the compound reduces expression of the non-wild type K- ras protein by preferentially binding to the non-wild type KRAS gene over the wild-type KRAS gene, and wherein the compound binds the non-wild-type KRAS gene at the single nucleotide polymorphism. In some embodiments, the compound reduces expression of the non-wild type K-ras protein by preferentially binding to a mRNA sequence transcribed from the non-wild type KRAS gene over a mRNA sequence transcribed from the wild type gene, wherein the mRNA sequence transcribed from the non-wild type gene comprises a nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject, and wherein the compound binds to the nucleobase that corresponds to the single nucleotide polymorphism of the non-wild type KRAS gene of the subject.
[00420] In some embodiments, the compound reduces transcription of the non-wild type KRAS gene in the subject. In some embodiments, the compound reduces translation of a mRNA sequence transcribed from the non-wild type KRAS gene in the subject. In some embodiments, the condition is cancer. In some embodiments, the condition is a human cancer. In some embodiments, the condition is cancer associated with a mutation in the non-wild type KRAS gene. In some embodiments, the condition is pancreatic ductal adenocarcinoma. In some embodiments, the condition is lung adenocarcinoma. In some embodiments, the condition is multiple myeloma. In some embodiments, the human cancer is pancreatic ductal adenocarcinoma. In some embodiments, the human cancer is lung adenocarcinoma. In some embodiments, the human cancer is multiple myeloma. In some embodiments, the human cancer associated with the non-wild type KRAS gene is HPAFII. In some embodiments, the human cancer associated with the non-wild type KRAS gene is CAPAN-II. In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein. In some embodiments, the non-wild type K-ras protein is K-ras G12D. In some embodiments, the non-wild type K-ras protein is K-ras G12V. In some embodiments, the non-wild type K-ras protein is K-ras G12C.
[00421] In some embodiments, the therapeutically-effective amount is about 0.01 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.05 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.1 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.2 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.3 mg/kg. In some embodiments, the therapeutically- effective amount is about 0.4 mg/kg. In some embodiments, the therapeutically-effective amount is about 0.5 mg/kg. In some embodiments, the administering is oral. In some embodiments, the administering is intravenous. In some embodiments, the administering is subcutaneous.
[00422] In some embodiments, the single nucleotide polymorphism results in a G12D mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12V mutation in the non-wild type K-ras protein. In some embodiments, the single nucleotide polymorphism results in a G12C mutation in the non-wild type K-ras protein.
[00423] In some embodiments, the subject is a vertebrate. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a subject is a non-human subject. In some embodiments, a subject is a veterinary subject.
Dosing
[00424] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The dosage (e.g., therapeutically-effective amount) for a compound described herein can be in any amount necessary.
[00425] A compound described herein can be present in a composition or a unit dose in a range of from about 1 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 25 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg. [00426] A compound described herein can be present in a composition or a unit dose in a range of from about 1 μg to about 2000 μg; from about 5 μg to about 1000 μg, from about 10 μg to about 25 μg, from about 50 μg to about 250 μg, from about 100 μg to about 200 μg, from about 1 μg to about 50 μg, from about 50 μg to about 100 μg, from about 100 μg to about 150 μg, from about 150 μg to about 200 μg, from about 200 μg to about 250 μg, from about 250 μg to about 300 μg, from about 300 μg to about 350 μg, from about 350 μg to about 400 μg, from about 400 μg to about 450 μg, from about 450 μg to about 500 μg, from about 500 μg to about 550 μg, from about 550 μg to about 600 μg, from about 600 μg to about 650 μg, from about 650 μg to about 700 μg, from about 700 μg to about 750 μg, from about 750 μg to about 800 μg, from about 800 μg to about 850 μg, from about 850 μg to about 900 μg, from about 900 μg to about 950 μg, or from about 950 μg to about 1000 μg.
[00427] A compound described herein can be present in a composition or a unit dose in an amount of about 0.001 mg, about 0.002 mg, about 0.003 mg, about 0.004 mg, about 0.005 mg, about 0.006 mg, about 0.007 mg, about 0.008 mg, about 0.009 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.
[00428] In some embodiments, a composition is present in a composition or a unit dose in an amount that is at least about 0.001 mg, at least about 0.002 mg, at least about 0.003 mg, at least about 0.004 mg, at least about 0.005 mg, at least about 0.006 mg, at least about 0.007 mg, at least about 0.008 mg, at least about 0.009 mg, at least about 0.01 mg, at least about 0.02 mg, at least about 0.03 mg, at least about 0.04 mg, at least about 0.05 mg, at least about 0.06 mg, at least about 0.07 mg, at least about 0.08 mg, at least about 0.09 mg, at least about 0.1 mg, at least about 0.2 mg, at least about 0.3 mg, at least about 0.4 mg, at least about 0.5 mg, at least about 0.6 mg, at least about 0.7 mg, at least about 0.8 mg, at least about 0.9 mg, at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, at least about 1800 mg, at least about 1850 mg, at least about 1900 mg, at least about 1950 mg, or at least about 2000 mg.
[00429] In some embodiments, a composition is present in a composition or a unit dose in an amount that is at most about 0.001 mg, at most about 0.002 mg, at most about 0.003 mg, at most about 0.004 mg, at most about 0.005 mg, at most about 0.006 mg, at most about 0.007 mg, at most about 0.008 mg, at most about 0.009 mg, at most about 0.01 mg, at most about 0.02 mg, at most about 0.03 mg, at most about 0.04 mg, at most about 0.05 mg, at most about 0.06 mg, at most about 0.07 mg, at most about 0.08 mg, at most about 0.09 mg, at most about 0.1 mg, at most about 0.2 mg, at most about 0.3 mg, at most about 0.4 mg, at most about 0.5 mg, at most about 0.6 mg, at most about 0.7 mg, at most about 0.8 mg, at most about 0.9 mg, at most about 1 mg, at most about 2 mg, at most about 3 mg, at most about 4 mg, at most about 5 mg, at most about 10 mg, at most about 15 mg, at most about 20 mg, at most about 25 mg, at most about 30 mg, at most about 35 mg, at most about 40 mg, at most about 45 mg, at most about 50 mg, at most about 55 mg, at most about 60 mg, at most about 65 mg, at most about 70 mg, at most about 75 mg, at most about 80 mg, at most about 85 mg, at most about 90 mg, at most about 95 mg, at most about 100 mg, at most about 125 mg, at most about 150 mg, at most about 175 mg, at most about 200 mg, at most about 250 mg, at most about 300 mg, at most about 350 mg, at most about 400 mg, at most about 450 mg, at most about 500 mg, at most about 550 mg, at most about 600 mg, at most about 650 mg, at most about 700 mg, at most about 750 mg, at most about 800 mg, at most about 850 mg, at most about 900 mg, at most about 950 mg, at most about 1000 mg, at most about 1050 mg, at most about 1100 mg, at most about 1150 mg, at most about 1200 mg, at most about 1250 mg, at most about 1300 mg, at most about 1350 mg, at most about 1400 mg, at most about 1450 mg, at most about 1500 mg, at most about 1550 mg, at most about 1600 mg, at most about 1650 mg, at most about 1700 mg, at most about 1750 mg, at most about 1800 mg, at most about 1850 mg, at most about 1900 mg, at most about 1950 mg, or at most about 2000 mg.
[00430] In some embodiments, a dose (e.g., a unit dose) is about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.007 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450 mg/kg, about 500 mg/kg, about 550 mg/kg, about 600 mg/kg, about 650 mg/kg, about 700 mg/kg, about 750 mg/kg, about 800 mg/kg, about 850 mg/kg, about 900 mg/kg, about 950 mg/kg, about 1000 mg/kg, about 1050 mg/kg, about 1100 mg/kg, about 1150 mg/kg, about 1200 mg/kg, about 1250 mg/kg, about 1300 mg/kg, about 1350 mg/kg, about 1400 mg/kg, about 1450 mg/kg, about 1500 mg/kg, about 1550 mg/kg, about 1600 mg/kg, about 1650 mg/kg, about 1700 mg/kg, about 1750 mg/kg, about 1800 mg/kg, about 1850 mg/kg, about 1900 mg/kg, about
1950 mg/kg, or about 2000 mg/kg based on body mass of a subject or a patient.
[00431] In some embodiments, a dose (e.g., a unit dose) is at least about 0.001 mg/kg, at least about 0.002 mg/kg, at least about 0.003 mg/kg, at least about 0.004 mg/kg, at least about 0.005 mg/kg, at least about 0.006 mg/kg, at least about 0.007 mg/kg, at least about 0.008 mg/kg, at least about 0.009 mg/kg, at least about 0.01 mg/kg, at least about 0.02 mg/kg, at least about 0.03 mg/kg, at least about 0.04 mg/kg, at least about 0.05 mg/kg, at least about 0.06 mg/kg, at least about 0.07 mg/kg, at least about 0.08 mg/kg, at least about 0.09 mg/kg, at least about 0.1 mg/kg, at least about 0.2 mg/kg, at least about 0.3 mg/kg, at least about 0.4 mg/kg, at least about 0.5 mg/kg, at least about 0.6 mg/kg, at least about 0.7 mg/kg, at least about 0.8 mg/kg, at least about 0.9 mg/kg, at least about 1 mg/kg, at least about 2 mg/kg, at least about 3 mg/kg, at least about 4 mg/kg, at least about 5 mg/kg, at least about 10 mg/kg, at least about 15 mg/kg, at least about 20 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 35 mg/kg, at least about 40 mg/kg, at least about 45 mg/kg, at least about 50 mg/kg, at least about 55 mg/kg, at least about 60 mg/kg, at least about 65 mg/kg, at least about 70 mg/kg, at least about 75 mg/kg, at least about 80 mg/kg, at least about 85 mg/kg, at least about 90 mg/kg, at least about 95 mg/kg, at least about 100 mg/kg, at least about 125 mg/kg, at least about 150 mg/kg, at least about 175 mg/kg, at least about 200 mg/kg, at least about 250 mg/kg, at least about 300 mg/kg, at least about 350 mg/kg, at least about 400 mg/kg, at least about 450 mg/kg, at least about 500 mg/kg, at least about 550 mg/kg, at least about 600 mg/kg, at least about 650 mg/kg, at least about 700 mg/kg, at least about 750 mg/kg, at least about 800 mg/kg, at least about 850 mg/kg, at least about 900 mg/kg, at least about 950 mg/kg, at least about 1000 mg/kg, at least about 1050 mg/kg, at least about 1100 mg/kg, at least about 1150 mg/kg, at least about 1200 mg/kg, at least about 1250 mg/kg, at least about 1300 mg/kg, at least about 1350 mg/kg, at least about 1400 mg/kg, at least about 1450 mg/kg, at least about 1500 mg/kg, at least about 1550 mg/kg, at least about 1600 mg/kg, at least about 1650 mg/kg, at least about 1700 mg/kg, at least about 1750 mg/kg, at least about 1800 mg/kg, at least about 1850 mg/kg, at least about 1900 mg/kg, at least about 1950 mg/kg, or at least about 2000 mg/kg based on body mass of a subject or a patient. [00432] In some embodiments, a dose (e.g., a unit dose) is at most about 0.001 mg/kg, at most about 0.002 mg/kg, at most about 0.003 mg/kg, at most about 0.004 mg/kg, at most about 0.005 mg/kg, at most about 0.006 mg/kg, at most about 0.007 mg/kg, at most about 0.008 mg/kg, at most about 0.009 mg/kg, at most about 0.01 mg/kg, at most about 0.02 mg/kg, at most about 0.03 mg/kg, at most about 0.04 mg/kg, at most about 0.05 mg/kg, at most about 0.06 mg/kg, at most about 0.07 mg/kg, at most about 0.08 mg/kg, at most about 0.09 mg/kg, at most about 0.1 mg/kg, at most about 0.2 mg/kg, at most about 0.3 mg/kg, at most about 0.4 mg/kg, at most about 0.5 mg/kg, at most about 0.6 mg/kg, at most about 0.7 mg/kg, at most about 0.8 mg/kg, at most about 0.9 mg/kg, at most about 1 mg/kg, at most about 2 mg/kg, at most about 3 mg/kg, at most about 4 mg/kg, at most about 5 mg/kg, at most about 10 mg/kg, at most about 15 mg/kg, at most about 20 mg/kg, at most about 25 mg/kg, at most about 30 mg/kg, at most about 35 mg/kg, at most about 40 mg/kg, at most about 45 mg/kg, at most about 50 mg/kg, at most about 55 mg/kg, at most about 60 mg/kg, at most about 65 mg/kg, at most about 70 mg/kg, at most about 75 mg/kg, at most about 80 mg/kg, at most about 85 mg/kg, at most about 90 mg/kg, at most about 95 mg/kg, at most about 100 mg/kg, at most about 125 mg/kg, at most about 150 mg/kg, at most about 175 mg/kg, at most about 200 mg/kg, at most about 250 mg/kg, at most about 300 mg/kg, at most about 350 mg/kg, at most about 400 mg/kg, at most about 450 mg/kg, at most about 500 mg/kg, at most about 550 mg/kg, at most about 600 mg/kg, at most about 650 mg/kg, at most about 700 mg/kg, at most about 750 mg/kg, at most about 800 mg/kg, at most about 850 mg/kg, at most about 900 mg/kg, at most about 950 mg/kg, at most about 1000 mg/kg, at most about 1050 mg/kg, at most about 1100 mg/kg, at most about 1150 mg/kg, at most about 1200 mg/kg, at most about 1250 mg/kg, at most about 1300 mg/kg, at most about 1350 mg/kg, at most about 1400 mg/kg, at most about 1450 mg/kg, at most about 1500 mg/kg, at most about 1550 mg/kg, at most about 1600 mg/kg, at most about 1650 mg/kg, at most about 1700 mg/kg, at most about 1750 mg/kg, at most about 1800 mg/kg, at most about 1850 mg/kg, at most about 1900 mg/kg, at most about 1950 mg/kg, or at most about 2000 mg/kg based on body mass of a subject or a patient.
[00433] In some embodiments, a dose (e.g., a unit dose) is from about 0.1 mg/kg to about 2000 mg/kg, from about 1 mg/kg to about 2000 mg/kg, from about 5 mg/kg to about 1000 mg/kg, from about 10 mg/kg to about 25 mg/kg, from about 50 mg/kg to about 250 mg/kg, from about 100 mg/kg to about 200 mg/kg, from about 1 mg/kg to about 50 mg/kg, from about 50 mg/kg to about 100 mg/kg, from about 100 mg/kg to about 150 mg/kg, from about 150 mg/kg to about 200 mg/kg, from about 200 mg/kg to about 250 mg/kg, from about 250 mg/kg to about 300 mg/kg, from about 300 mg/kg to about 350 mg/kg, from about 350 mg/kg to about 400 mg/kg, from about 400 mg/kg to about 450 mg/kg, from about 450 mg/kg to about 500 mg/kg, from about 500 mg/kg to about 550 mg/kg, from about 550 mg/kg to about 600 mg/kg, from about 600 mg/kg to about 650 mg/kg, from about 650 mg/kg to about 700 mg/kg, from about 700 mg/kg to about 750 mg/kg, from about 750 mg/kg to about 800 mg/kg, from about 800 mg/kg to about 850 mg/kg, from about 850 mg/kg to about 900 mg/kg, from about 900 mg/kg to about 950 mg/kg, from about 950 mg/kg to about 1000 mg/kg, about 1 μg/kg to about 2000 μg/kg; from about 5 μg/kg to about 1000 μg/kg, from about 10 μg/kg to about 25 μg/kg, from about 50 μg/kg to about 250 μg/kg, from about 100 μg/kg to about 200 μg/kg, from about 1 μg/kg to about 50 μg/kg, from about 50 μg/kg to about 100 μg/kg, from about 100 μg/kg to about 150 μg/kg, from about 150 μg/kg to about 200 μg/kg, from about 200 μg/kg to about 250 μg/kg, from about 250 μg/kg to about 300 μg/kg, from about 300 μg/kg to about 350 μg/kg, from about 350 μg/kg to about 400 μg/kg, from about 400 μg/kg to about 450 μg/kg, from about 450 μg/kg to about 500 μg/kg, from about 500 μg/kg to about 550 μg/kg, from about 550 μg/kg to about 600 μg/kg, from about 600 μg/kg to about 650 μg/kg, from about 650 μg/kg to about 700 μg/kg, from about 700 μg/kg to about 750 μg/kg, from about 750 μg/kg to about 800 μg/kg, from about 800 μg/kg to about 850 μg/kg, from about 850 μg/kg to about 900 μg/kg, from about 900 μg/kg to about 950 μg/kg, or from about 950 μg/kg to about 1000 μg/kg based on body mass of a subject or a patient.
[00434] Pharmaceutical compositions and formulations described herein can comprise, for example, a compound provided herein at any suitable concentration. A formulation can comprise a composition provided herein at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 250 mg/mL, about 300 mg/mL, about 350 mg/mL, about 400 mg/mL, about 450 mg/mL, about 500 mg/mL, about 550 mg/mL, about 600 mg/mL, about 650 mg/mL, about 700 mg/mL, about 750 mg/mL, about 800 mg/mL, about 850 mg/mL, about 900 mg/mL, about 950 mg/mL, about 1000 mg/mL, about 1050 mg/mL, about 1100 mg/mL, about 1150 mg/mL, about 1200 mg/mL, about 1250 mg/mL, about 1300 mg/mL, about 1350 mg/mL, about 1400 mg/mL, about 1450 mg/mL, about 1500 mg/mL, about 1550 mg/mL, about 1600 mg/mL, about 1650 mg/mL, about 1700 mg/mL, about 1750 mg/mL, about 1800 mg/mL, about 1850 mg/mL, about 1900 mg/mL, about 1950 mg/mL, or about 2000 mg/mL.
[00435] In some embodiments, a formulation provided herein comprises a compound provided herein at a concentration of at least about 0.001 mg/mL, at least about 0.002 mg/mL, at least about 0.003 mg/mL, at least about 0.004 mg/mL, at least about 0.005 mg/mL, at least about 0.006 mg/mL, at least about 0.007 mg/mL, at least about 0.008 mg/mL, at least about 0.009 mg/mL, at least about 0.01 mg/mL, at least about 0.02 mg/mL, at least about 0.03 mg/mL, at least about 0.04 mg/mL, at least about 0.05 mg/mL, at least about 0.06 mg/mL, at least about 0.07 mg/mL, at least about 0.08 mg/mL, at least about 0.09 mg/mL, at least about 0.1 mg/mL, at least about 0.2 mg/mL, at least about 0.3 mg/mL, at least about 0.4 mg/mL, at least about 0.5 mg/mL, at least about 0.6 mg/mL, at least about 0.7 mg/mL, at least about 0.8 mg/mL, at least about 0.9 mg/mL, at least about 1 mg/mL, at least about 2 mg/mL, at least about 3 mg/mL, at least about 4 mg/mL, at least about 5 mg/mL, at least about 10 mg/mL, at least about 15 mg/mL, at least about 20 mg/mL, at least about 25 mg/mL, at least about 30 mg/mL, at least about 35 mg/mL, at least about 40 mg/mL, at least about 45 mg/mL, at least about 50 mg/mL, at least about 55 mg/mL, at least about 60 mg/mL, at least about 65 mg/mL, at least about 70 mg/mL, at least about 75 mg/mL, at least about 80 mg/mL, at least about 85 mg/mL, at least about 90 mg/mL, at least about 95 mg/mL, at least about 100 mg/mL, at least about 125 mg/mL, at least about 150 mg/mL, at least about 175 mg/mL, at least about 200 mg/mL, at least about 250 mg/mL, at least about 300 mg/mL, at least about 350 mg/mL, at least about 400 mg/mL, at least about 450 mg/mL, at least about 500 mg/mL, at least about 550 mg/mL, at least about 600 mg/mL, at least about 650 mg/mL, at least about 700 mg/mL, at least about 750 mg/mL, at least about 800 mg/mL, at least about 850 mg/mL, at least about 900 mg/mL, at least about 950 mg/mL, at least about 1000 mg/mL, at least about 1050 mg/mL, at least about 1100 mg/mL, at least about 1150 mg/mL, at least about 1200 mg/mL, at least about 1250 mg/mL, at least about 1300 mg/mL, at least about 1350 mg/mL, at least about 1400 mg/mL, at least about 1450 mg/mL, at least about 1500 mg/mL, at least about 1550 mg/mL, at least about 1600 mg/mL, at least about 1650 mg/mL, at least about 1700 mg/mL, at least about 1750 mg/mL, at least about 1800 mg/mL, at least about 1850 mg/mL, at least about 1900 mg/mL, at least about 1950 mg/mL, or at least about 2000 mg/mL.
[00436] In some embodiments, a formulation provided herein comprises a compound provided herein at a concentration of at most about 0.002 mg/mL, at most about 0.003 mg/mL, at most about 0.004 mg/mL, at most about 0.005 mg/mL, at most about 0.006 mg/mL, at most about 0.007 mg/mL, at most about 0.008 mg/mL, at most about 0.009 mg/mL, at most about 0.01 mg/mL, at most about 0.02 mg/mL, at most about 0.03 mg/mL, at most about 0.04 mg/mL, at most about 0.05 mg/mL, at most about 0.06 mg/mL, at most about 0.07 mg/mL, at most about 0.08 mg/mL, at most about 0.09 mg/mL, at most about 0.1 mg/mL, at most about 0.2 mg/mL, at most about 0.3 mg/mL, at most about 0.4 mg/mL, at most about 0.5 mg/mL, at most about 0.6 mg/mL, at most about 0.7 mg/mL, at most about 0.8 mg/mL, at most about 0.9 mg/mL, at most about 1 mg/mL, at most about 2 mg/mL, at most about 3 mg/mL, at most about 4 mg/mL, at most about 5 mg/mL, at most about 10 mg/mL, at most about 15 mg/mL, at most about 20 mg/mL, at most about 25 mg/mL, at most about 30 mg/mL, at most about 35 mg/mL, at most about 40 mg/mL, at most about 45 mg/mL, at most about 50 mg/mL, at most about 55 mg/mL, at most about 60 mg/mL, at most about 65 mg/mL, at most about 70 mg/mL, at most about 75 mg/mL, at most about 80 mg/mL, at most about 85 mg/mL, at most about 90 mg/mL, at most about 95 mg/mL, at most about 100 mg/mL, at most about 125 mg/mL, at most about 150 mg/mL, at most about 175 mg/mL, at most about 200 mg/mL, at most about 250 mg/mL, at most about 300 mg/mL, at most about 350 mg/mL, at most about 400 mg/mL, at most about 450 mg/mL, at most about 500 mg/mL, at most about 550 mg/mL, at most about 600 mg/mL, at most about 650 mg/mL, at most about 700 mg/mL, at most about 750 mg/mL, at most about 800 mg/mL, at most about 850 mg/mL, at most about 900 mg/mL, at most about 950 mg/mL, at most about 1000 mg/mL, at most about 1050 mg/mL, at most about 1100 mg/mL, at most about 1150 mg/mL, at most about 1200 mg/mL, at most about 1250 mg/mL, at most about 1300 mg/mL, at most about 1350 mg/mL, at most about 1400 mg/mL, at most about 1450 mg/mL, at most about 1500 mg/mL, at most about 1550 mg/mL, at most about 1600 mg/mL, at most about 1650 mg/mL, at most about 1700 mg/mL, at most about 1750 mg/mL, at most about 1800 mg/mL, at most about 1850 mg/mL, at most about 1900 mg/mL, at most about 1950 mg/mL, or at most about 2000 mg/mL.
[00437] In some embodiments, a formulation provided herein comprises a compound provided herein at a concentration of about 1 mg/mL to about 2000 mg/mL; from about 5 mg/mL to about 1000 mg/mL, from about 10 mg/mL to about 25 mg/mL, from about 50 mg/mL to about 250 mg/mL, from about 100 mg/mL to about 200 mg/mL, from about 1 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 100 mg/mL, from about 100 mg/mL to about 150 mg/mL, from about 150 mg/mL to about 200 mg/mL, from about 200 mg/mL to about 250 mg/mL, from about 250 mg/mL to about 300 mg/mL, from about 300 mg/mL to about 350 mg/mL, from about 350 mg/mL to about 400 mg/mL, from about 400 mg/mL to about 450 mg/mL, from about 450 mg/mL to about 500 mg/mL, from about 500 mg/mL to about 550 mg/mL, from about 550 mg/mL to about 600 mg/mL, from about 600 mg/mL to about 650 mg/mL, from about 650 mg/mL to about 700 mg/mL, from about 700 mg/mL to about 750 mg/mL, from about 750 mg/mL to about 800 mg/mL, from about 800 mg/mL to about 850 mg/mL, from about 850 mg/mL to about 900 mg/mL, from about 900 mg/mL to about 950 mg/mL, from about 950 mg/mL to about 1000 mg/mL, about 1 μg/mL to about 2000 μg/mL; from about 5 μg/mL to about 1000 μg/mL, from about 10 μg/mL to about 25 μg/mL, from about 50 μg/mL to about 250 pg/mL, from about 100 pg/mL to about 200 pg/mL, from about 1 pg/mL to about 50 μg/mL, from about 50 μg/mL to about 100 μg/mL, from about 100 μg/mL to about 150 μg/mL, from about 150 μg/mL to about 200 μg/mL, from about 200 μg/mL to about 250 μg/mL, from about 250 μg/mL to about 300 μg/mL, from about 300 μg/mL to about 350 μg/mL, from about 350 μg/mL to about 400 μg/mL, from about 400 μg/mL to about 450 μg/mL, from about 450 μg/mL to about 500 μg/mL, from about 500 μg/mL to about 550 μg/mL, from about 550 μg/mL to about 600 μg/mL, from about 600 μg/mL to about 650 μg/mL, from about 650 μg/mL to about 700 μg/mL, from about 700 μg/mL to about 750 μg/mL, from about 750 μg/mL to about 800 μg/mL, from about 800 μg/mL to about 850 μg/mL, from about 850 μg/mL to about 900 μg/mL, from about 900 μg/mL to about 950 μg/mL, or from about 950 μg/mL to about 1000 μg/mL.
[00438] In some embodiments, a formulation of the disclosure delivers about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg AED of a compound of the disclosure. In some embodiments, a formulation of the disclosure delivers about 0.1 mg/kg AED of a compound of the disclosure. In some embodiments, a formulation of the disclosure delivers about 0.2 mg/kg AED of a compound of the disclosure. In some embodiments, a formulation of the disclosure delivers about 03 mg/kg AED of a compound of the disclosure.
[00439] An approximate dose can be predicted or determined on the basis of data existing in other species. In some embodiments, allometric scaling can be used to exchange a drug dose based on normalization of dose to body surface area. Allometric scaling considers the sizes of individual species based on body surface area, which is related to metabolic rate of an animal that is established through evolutionary adaptation of animals to their size. A no observed adverse effect level (NOAEL) is first determined in an animal species, the NOAEL is converted to a human equivalent dose (HED), an appropriate animal species is selected, a safety factor is applied, and a pharmacologically active dose is determined.
[00440] NOAEL, the highest dose level that does not cause significant adverse effects, is a typical index for safety obtained from animal experiments to determine a safe starting dose. NOAEL values can be converted to HED on the basis of the body surface correction factor using appropriate scaling factors from animal species. TABLE 5 lists HED calculation guidelines based on body surface areas. HED is determined using the equation:
HED (mg/kg) = Animal NOAEL (mg/kg) x (Weightanimal[kg]/Weighthuman[kg])(1-067) [00441] The HED is divided by a factor value of 10 to increase safety of the first human dose. The safety factor is accountable for differences in physiological and biological processes between human and animal species.
[00442] The correction factor (Km) is estimated by dividing the average body weight (kg) of a species to its body surface area (m2). The Km factor values of various animal species of TABLE 5 is used to estimate the HED as:
HED (mg/kg) = Animal doses (mg/kg) x (Animal Km/Human Km); or HED (mg/kg) = Animal doses (mg/kg) x Km ratio [00443] However, conversion between species based on mg/m2 is not supported for drugs administered by topical, nasal, subcutaneous, or intramuscular routes, as well as proteins administered parenterally with molecular weight >100,000 Daltons. TABLE 5
To convert To convert animal dose dose in in mg/kg to HED in
Reference Working Body mg/kg to mg/kg, either
Species body weight weight surface area dose in
Divide Multiply
(kg) range (kg) (m2) mg/m2, animal dose animal dose multiply by by by
Km
Human 60 - 1.62 37 - -
Mouse 0.02 0 011 0.034 0.007 3 12.3 0.081
Hamster 0.08 0 047 0.157 0.016 5 7.4 0.135
Rat 0.15 0 08 0.27 0.025 6 6.2 0.162
Ferret 0.30 0 16 0.54 0.043 7 5.3 0.189
Guinea Pig 0.40 0 208 0.700 0.05 8 4.6 0.216
Rabbit 1.8 090 3.0 0.15 12 3.1 0.324
Dog 10 5-17 0.50 20 1.8 0.541
Monkeys 3 1 4 4.9 0.25 12 3.1 0.324
(rhesus)
Marmoset 0.35 0 14 0.72 0.06 6 6.2 0.162
Squirrel 0.60 029 0.97 0.09 7 5.3 0.189
Monkey
Baboon 12 7-23 0.60 20 1.8 0.541
Micro pig 20 10-33 0.74 27 1.4 0.730
Mini pig 40 25-64 1.14 35 1.1 0.946
[00444] TABLE 6 provides animal equivalent dose (AED) calculation guidelines based on body surface area. The animal equivalent dose (AED) can also be calculated on the basis of body surface area by either dividing or multiplying the human dose (mg/kg) by the Km ratio provided in TABLE 6. AED can be calculated using the equation:
AED (mg/kg) = Human doses (mg/kg) x Km ratio TABLE 6
To convert dose To convert human dose in mg/kg to
Reference body in mg/kg to dose AED in mg/kg, either
Species weight (kg) in mg/m2, divide Multiply human Divide human by Km dose by dose by
Human 60 37 - -
Mouse 0.02 3 12.3 0.081
Hamster 0.08 5 7.4 0.135
Rat 0.15 6 6.2 0.162
Ferret 0.30 7 5.3 0 189
Guinea Pig 0.40 8 4.6 0.216
Rabbit 1.8 12 3.1 0.324
Dog 10 20 1.8 0.541
Monkeys (rhesus) 3 12 3.1 0.324
Marmoset 0.35 6 6.2 0.162
Squirrel Monkey 0.60 7 5.3 0.189
Baboon 12 20 1.8 0.541
Micro pig 20 27 1.4 0.730
Mini pig 40 35 1.1 0.946
[00445] For parenteral administration, HED conversion (mg/kg) is also based on body surface area normalization. The conversion can be made by dividing the NOAEL in appropriate species by the conversion factor. TABLE 7 provides guidelines for maximum injection volume, by species, site location, and gauge size. Injection volume of parenteral formulation is calculated by the following equation:
Injection volume (mL) = [Animal weight (kg) x Animal doses (mg/kg)] / Concentration (mg/kg)
TABLE 7
Route
Subcutaneous Intramuscular Intraperitoneal Intravenous Intradermal
Max Max Max Max Max
Species injection Gauge injection Gauge injection Gauge injection Gauge injection Gauge
Site Site Site Site Site volume size volume size volume size volume size volume size
(mL) (mL) (mL) (mL) (mL)
Upper arm,
Deltoid, abdomen,
Human <2 25-31 2-5 vastus 21-23 2-5 Peritoneum - <250 Vein 18-20 <0.10 Dermis 25-26 thigh, lateralis buttock
Back
Quadriceps,
(scruff), Lateral tail Lateral
Mouse 1-2 <20 <0.1 posterior 25 2-3 25 <0.2 Lateral tail vein 25 <0.05 - lower vein abdomen thigh abdomen
Dorsum hind limb, Lower left Lateral tarsal vein,
Hamster 3-4 between <20 <0.1 25 2-3 25-56 <0.2 26 <0.05 - - caudal thigh quadrant cephalic/lingual vein scapula
Lower left
Back quadrant
(scruff), quadriceps, Lateral Lateral
Rat 5-10 <20 <0.3 25-56 5-10 24 <0.5 24-27 <0.05 - lower hamstrings tail/saphenous vein abdomen abdomen
Dorsum hind limb, Cephalic, Cephalic/saphenous
Dog 100-200 between 22 2-5 22-25 100-200 22-25 <100 21 - - - caudal thigh saphenous vein scapula
Lind limb,
Dorsum Dorsum
Guinea caudal thigh, Lower left Lateral saphenous
5-10 between 25 0.3 25 10-15 25 10-15 26-27 - along 25
Pig lumbar quadrant vein scapula flank muscles
Dorsum
Hind limb, Lower left
Rabbit 10-50 Dorsum 22-25 <0.5 22-25 50-100 22 <5 Marginal ear vein 25 <0.1 along 25 caudal thigh quadrant flank
Monkey Hind limb,
10-30 Dorsum 22-23 1-3 22-23 25-50 Peritoneum 20 5-10 Saphenous vein 22-23 - - -
(Rhesus) caudal thigh
Quadriceps,
Squirrel
5-10 Scuff 20 1-3 posterior 20 25-50 Peritoneum 20 0.5-1 Femoral vein 21 - - -
Monkey thigh, triceps
Pharmaceutical compositions
[00446] A pharmaceutical composition of the disclosure can be used, for example, before, during, or after treatment of a subject with, for example, another pharmaceutical agent.
[00447] Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals. In some embodiments, a subject is a patient.
[00448] A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration.
[00449] A pharmaceutical composition can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release. [00450] For oral administration, pharmaceutical compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject. Non-limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hy droxy ethyl- 1- piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC). Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremophor, DMSO, and potassium phosphate buffer.
[00451] Pharmaceutical preparations can be formulated for intravenous administration. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [00452] The active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[00453] The compounds of the disclosure can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject. The compounds of the disclosure can be applied to an accessible body cavity.
[00454] The compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, and PEG. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be melted.
[00455] In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein can be administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
[00456] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulations can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.
[00457] The pharmaceutical compositions can include at least one pharmaceutically-acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically- acceptable salt form. Pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[00458] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, for example, gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. [00459] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.
[00460] Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.
[00461] A composition of the disclosure can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
[00462] In some, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.
[00463] A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16 or about 24 hours.
[00464] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.
[00465] Multiple therapeutic agents can be administered in any order or simultaneously. In some embodiments, a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The agents can be packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month. [00466] Therapeutic agents described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a therapeutic agent can vary. For example, the compositions can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen a likelihood of the occurrence of the disease or condition. The compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the therapeutic agents can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as by any route described herein using any formulation described herein.
[00467] A compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years. The length of treatment can vary for each subject.
[00468] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged injectables, vials, or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative. Formulations for injection can be presented in unit dosage form, for example, in ampoules, or in multi dose containers with a preservative.
[00469] Pharmaceutical compositions provided herein, can be administered in conjunction with other therapies, for example, chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins. The other agents can be administered prior to, after, or concomitantly with the pharmaceutical compositions.
[00470] Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in unit dosage form suitable for single administration of a precise dosage.
[00471] For solid compositions, nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.
[00472] Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of the disclosure include anti-infectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics/antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations. [00473] Compounds can be delivered via liposomal technology. The use of liposomes as drug carriers can increase the therapeutic index of the compounds. Liposomes are composed of natural phospholipids, and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine). A liposome design can employ surface ligands for attaching to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to reduce a likelihood of developing premature degradation and toxicity to non-target tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, smallsized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally, liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells. Non-limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.
[00474] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti -adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.
[00475] Compositions of the disclosure can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration/use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. The written material can be a label. In some embodiments, the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies. [00476] In some embodiments, the disclosure provides a pharmaceutical composition comprising, in a unit dosage form: a) a pharmaceutically-acceptable excipient; and b) an amount of a compound that is therapeutically-effective for treatment of a cancer associated with a KRAS mutation, the compound comprising a structure that binds to a sequence of nucleic acids encoding a KRAS gene, wherein the structure is:
N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1ξ-
Figure imgf000227_0001
t he number of units with variables defined independently is at least 3;
N-Terminus is H, acyl, a group that together with the nitrogen atom to which A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each Ralph a is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle;
C-Terminus is OH, OMe, or NH2
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent;
L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof. [00477] In some embodiments, PEP1 is absent. In some embodiments, PEP1 is the peptide sequence. In some embodiments, the peptide sequence of PEP 1 is a nuclear localization sequence. In some embodiments, PEP1 is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1). In some embodiments, PEP1 is Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2). In some embodiments, PEP1 is -Ala-Lys-Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 77). In some embodiments, PEP1 is -Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 78). In some embodiments, PEP1 is -Arg-Arg-. In some embodiments, PEP1 is -Arg-Phe-Gln-Ile-Leu-Tyr-Arg- (SEQ ED NO: 86). In some embodiments, PEP2 is absent. In some embodiments, PEP2 is the peptide sequence. In some embodiments, the peptide sequence of PEP2 is a nuclear localization sequence. In some embodiments, PEP2 is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1). In some embodiments, PEP2 is Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2). In some embodiments, PEP2 is -Arg-Arg-. In some embodiments, PEP2 is -Arg-Phe-Gln-Ile-Leu-Tyr- Arg- (SEQ ID NO: 86).
[00478] In some embodiments, SOLI is absent. In some embodiments, SOL1 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL1 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL1 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOLI is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL1 is a polyethyleneglycol group. In some embodiments, the water- solubilizing group of SOL1 is -Arg-Arg-NH(CH2)2C(0)-Arg-Arg-. [00479] In some embodiments, the sequence of nucleic acids encoding the KRAS gene is a mRNA sequence. In some embodiments, the sequence of nucleic acids encoding the KRAS gene is a DNA sequence.
[00480] In some embodiments, the water-solubilizing group of SOLI is a group of formula:
Figure imgf000228_0001
R1a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), orN(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00481] In some embodiments, the water-solubilizing group of SOL1 is a group of formula: wherein p is an integer that is 1-1,000. In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8. In some embodiments, p is an integer that is 7. [00482] In some embodiments, SOL2 is absent. In some embodiments, SOL2 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL2 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL2 is a polyethyleneglycol group. In some embodiments, the water- solubilizing group of SOL2 is -Arg-Arg-NH(CH2)2C(0)-Arg-Arg-. [00483] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
R1a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group; R3a is H, alkyl, or a nitrogen atom protecting group; R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), orN(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00484] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000230_0001
wherein p is an integer that is 1-1,000. In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8. In some embodiments, p is an integer that is 7. [00485] In some embodiments, PNA1 is the peptide nucleic acid sequence. In some embodiments, PNA2 is the peptide nucleic acid sequence.
[00486] In some embodiments, L1 is the linker group. In some embodiments, the linker group of L1 is cleavable. In some embodiments, the linker group of L1 is non-cleavable. In some embodiments, the linker group of L1 is a peptide sequence. In some embodiments, the linker group of L1 is a polyamine sequence. In some embodiments, the linker group of L1 is a polyamide sequence. In some embodiments, the linker group of LI is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L1 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L1 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L1 is a residue of oxalic acid. In some embodiments, the linker group of L1 is a residue of succinic acid. In some embodiments, the linker group of L1 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L1 is - NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-. In some embodiments, the linker group of L1 is -NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(O)-. In some embodiments, the linker group of LI is -Arg-NH(CH2)5C(O)-. In some embodiments, the linker group of L1 is - NH(CH2)5C(O)- In some embodiments, the linker group of LI is -NH(CH2)2C(O)-Arg- NH(CH2)5C(O)NH(CH2)2C(O)-. In some embodiments, the linker group of L1 is - NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00487] In some embodiments, L2 is the linker group. In some embodiments, the linker group of L2 is cleavable. In some embodiments, the linker group of L2 is non-cleavable. In some embodiments, the linker group of L2 is a peptide sequence. In some embodiments, the linker group of L2 is a polyamine sequence. In some embodiments, the linker group of L2 is a polyamide sequence. In some embodiments, the linker group of L2 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L2 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L2 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L2 is a residue of oxalic acid. In some embodiments, the linker group of L2 is a residue of succinic acid. In some embodiments, the linker group of L2 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L2 is - NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-. In some embodiments, the linker group of L2 is -NHCH(COOO)C(CH3)2S-SCH2CH(1SIH2)C(0)-. In some embodiments, the linker group of L2 is -Arg-NH(CH2)5C(O)-. In some embodiments, the linker group of L2 is - NH(CH2)5C(O)-. In some embodiments, the linker group of L2 is -NH(CH2)2C(O)-Arg- NH(CH2)5C(O)KH(CH2)2C(O)-. In some embodiments, the linker group of L2 is - NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00488] In some embodiments, L3 is the linker group. In some embodiments, the linker group of L3 is cleavable. In some embodiments, the linker group of L3 is non-cleavable. In some embodiments, the linker group of L3 is a peptide sequence. In some embodiments, the linker group of L3 is a polyamine sequence. In some embodiments, the linker group of L3 is a polyamide sequence. In some embodiments, the linker group of L3 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L3 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L3 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L3 is a residue of oxalic acid. In some embodiments, the linker group of L3 is a residue of succinic acid. In some embodiments, the linker group of L3 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L3 is - NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-. In some embodiments, the linker group of L3 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(O)-. In some embodiments, the linker group of L3 is -Arg-NH(CH2)5C(O)-. In some embodiments, the linker group of L3 is - NH(CH2)5C(O)-. In some embodiments, the linker group of L3 is -NH(CH2)2C(O)-Arg- NH(CH2)5C(O)NH(CH2)2C(O)-. In some embodiments, the linker group of L3 is - NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00489] In some embodiments, L4 is the linker group. In some embodiments, the linker group of L4 is cleavable. In some embodiments, the linker group of L4 is non-cleavable. In some embodiments, the linker group of L4 is a peptide sequence. In some embodiments, the linker group of L4 is a polyamine sequence. In some embodiments, the linker group of L4 is a polyamide sequence. In some embodiments, the linker group of L4 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L4 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L4 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L4 is a residue of oxalic acid. In some embodiments, the linker group of L4 is a residue of succinic acid. In some embodiments, the linker group of L4 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L4 is - NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-. In some embodiments, the linker group of L4 is -NHCH(COOH)C(CH3)2S-SCH2CH(1SIH2)C(O)-. In some embodiments, the linker group of L4 is -Arg-NH(CH2)5C(O)-. In some embodiments, the linker group of L4 is - NH(CH2)5C(O)-. In some embodiments, the linker group of L4 is -NH(CH2)2C(O)-Arg- NH(CH 2)5C(O)NH(CH2)2C(O)-. In some embodiments, the linker group of L4 is - NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00490] In some embodiments, L5 is the linker group. In some embodiments, the linker group of L5 is cleavable. In some embodiments, the linker group of L5 is non-cleavable. In some embodiments, the linker group of L5 is a peptide sequence. In some embodiments, the linker group of L5 is a polyamine sequence. In some embodiments, the linker group of L5 is a polyamide sequence. In some embodiments, the linker group of L5 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L5 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L5 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L5 is a residue of oxalic acid. In some embodiments, the linker group of L5 is a residue of succinic acid. In some embodiments, the linker group of L5 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L5 is - NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-. In some embodiments, the linker group of L5 is -NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(O)-. In some embodiments, the linker group of L5 is -Arg-NH(CH2)5C(O)-. In some embodiments, the linker group of L5 is - NH(CH2)5C(O)-. In some embodiments, the linker group of L5 is -NH(CH2)2C(O)-Arg- NH(CH2)5C(O)NH(CH2)2C(O)-. In some embodiments, the linker group of L5 is - NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00491] In some embodiments, L6 is the linker group. In some embodiments, the linker group of L 6 is cleavable. In some embodiments, the linker group of L6 is non-cleavable. In some embodiments, the linker group of L6 is a peptide sequence. In some embodiments, the linker group of L6 is a polyamine sequence. In some embodiments, the linker group of L6 is a polyamide sequence. In some embodiments, the linker group of L6 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L6 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L6 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L6 is a residue of oxalic acid. In some embodiments, the linker group of L6 is a residue of succinic acid. In some embodiments, the linker group of L6 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L6 is - NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-. In some embodiments, the linker group of L6 is -NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(O)-. In some embodiments, the linker group of L6 is -Arg-NH(CH2)5C(O)-. In some embodiments, the linker group of L6 is - NH(CH2)5C(O)-. In some embodiments, the linker group of L6 is -NH(CH2)2C(O)-Arg- NH(CH2)5C(O)NH(CH2)2C(OO-. In some embodiments, the linker group of L6 is - NH(CH2)5C(0)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00492] In some embodiments, the structure is:
N-Terminus wherein: the number of units with variables defined independently is at least 3;
N-Terminus is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each Ralph a is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; and
C-Terminus is OH, OMe, NH2, or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
[00493] In some embodiments, the structure is: [00494] In some embodiments, the structure binds to a nucleic acid sequence encoding a KRAS gene by interactions between the heterocycles of the R2 groups and nucleobases of the KRAS gene. In some embodiments, the KRAS gene is a non-wild type KRAS gene. In some embodiments, the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism In some embodiments, the single nucleotide polymorphism causes a mutation that is G12D. In some embodiments, the single nucleotide polymorphism causes a mutation that is G12V. In some embodiments, the single nucleotide polymorphism causes a mutation that is G12C. In some embodiments, the non-wild type KRAS gene encodes for expression of a non-wild type K-ras protein, wherein the non-wild type K-ras protein differs from a wild type K-ras protein in a single amino acid residue.
[00495] In some embodiments, the number of units with variables defined independently is 3- 1,000. In some embodiments, the number of units with variables defined independently is 3-100. In some embodiments, the number of units with variables defined independently is 3-50. In some embodiments, the number of units with variables defined independently is 3, 4, 5, 6, 7, 8, embodiments, the number of units with variables defined independently is at least 11. In some embodiments, the number of units with variables defined independently is 11-1,000. In some embodiments, the number of units with variables defined independently is 11-100. In some embodiments, the number of units with variables defined independently is 11-50. In some embodiments, the number of units with variables defined independently is 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[00496] In some embodiments, each R1 is independently alkyl that is unsubstituted. In some embodiments, each alkyl that is unsubstituted is independently methyl, ethyl, prop-1-yl, prop-2- yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent-1-yl. In some embodiments, each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-1-yl, or but-2-yl. In some embodiments, each R1 is independently alkyl that is substituted. In some embodiments, each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N -methylguanidino group, or an amido group. In some embodiments, each alkyl that is substituted is independently hydroxymethyl, 1- hydroxyeth-1-yl, sulfhydrylmethyl, 2-thiomethyleth-1-yl, 4-aminobut-1-yl, 3-aminoprop-1-yl, 1- H -imidazol-ylmethyl, 1 -H -indol-3-ylmethyl, benzyl, 4-hydroxyphen-1-ylmethyl, 2- carboxylatoeth-1-yl, 3-carboxylatoprop-1-yl, 3 -guani dinoprop- 1-yl, 4-guanidinobut-1-yl, 2- carbamoyleth-1-yl, or 3-carbamoylprop-1-yl. In some embodiments, each R1 is independently H, hydroxylmethyl, or 4-guanidinobut- 1yl. In some embodiments, at least one iteration of R1 is hydroxylmethyl. In some embodiments, at least a third of the iterations of R1 are hydroxylmethyl. In some embodiments, at least half the iterations ofR1 are hydroxylmethyl. [00497] In some embodiments, each Ralpha is independently alkyl that is unsubstituted. In some embodiments, each alkyl that is unsubstituted is independently methyl, ethyl, prop- 1-yl, prop-2- yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent-1-yl. In some embodiments, each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, or but-2-yl.
[00498] In some embodiments, each Ralpha is independently alkyl that is substituted. In some embodiments, each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, - NH2 a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a l'-methylguanidino group, or an amido group. In some embodiments, each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-1-yl, sulfhydrylmethyl, 2-thiomethyleth-1-yl, 4-aminobut-1-yl, 3- aminoprop-1-yl, 1 -H -imidazol-4-yl methyl, 1 -H -indol-3-ylmethyl, benzyl, 4-hydroxyphen-1- ylmethyl, 2-carboxylatoeth-1-yl, 3-carboxylatoprop-1-yl, 3-guani dinoprop- 1-yl, 4-guanidinobut- 1-yl, 2-carbamoyleth-1-yl, or 3-carbamoylprop-1-yl.
[00499] In some embodiments, each Ralpha is independently H, 3 -guani dinoprop- 1-yl, or 4- guanidinobut-l-yl. In some embodiments, at least one iteration of Ralpha is 3 -guani dinoprop- 1-yl. In some embodiments, at least a third of the iterations of Ralpha are 3 -guani dinoprop- 1-yl. In some embodiments, at least half the iterations of Ralpha are 3 -guani dinoprop- 1-yl.
[00500] In some embodiments, of the units with variables defined independently, counting fromN-Terminus, the first, third, sixth, ninth, eleventh, thirteenth, sixteenth, nineteenth, and twenty- second units, independently if present, are each 3-guanidinoprop-1-yl.
[00501] In some embodiments, at least a third of the R2 groups in the structure are methyl substituted with a heterocycle. In some embodiments, at least half of the R2 groups in the structure are methyl substituted with a heterocycle. In some embodiments, the heterocycles of the R2 groups are nucleobases or analogues of nucleobases. In some embodiments, at least one of the heterocycles of the R2 groups is a divalent nucleobase. In some embodiments, the heterocycles of the R2 groups are divalent nucleobases. In some embodiments, the heterocycles of the R2 groups are each independently:
Figure imgf000236_0001
[00502] In some embodiments, each R2 is independently: methyl, OMe,
Figure imgf000236_0002
[00503] In some embodiments, the N-terminus is H. In some embodiments, the N-terminus is acyl. In some embodiments, the N-terminus is the biological agent. In some embodiments, the biological agent is a vitamin E group. In some embodiments, the biological agent is an O-bound tocopherol group. In some embodiments, C-Terminus is NH2. In some embodiments, C- Terminus is -Pro-Lys-Lys-Lys-Arg-Lys-Val-NH2.
EMBODIMENTS
[00504] The following non-limiting embodiments in numbered paragraph form provide illustrative examples of the invention, but do not limit the scope of the invention.
[00505] A compound comprising a structure, wherein the structure interferes with expression of a cancer causing protein, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(O)-alkyl; and iii) guanidinoalkyl.
[00506] A compound comprising a structure, wherein the structure interferes with expression of a cancer causing protein , wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guani dinoalkyl.
[00507] A compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(O)-alkyl; and iii) guani dinoalkyl. [00508] A compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl.
[00509] A compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a KRAS gene, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH.
[00510] A compound comprising a structure, wherein the structure interferes with expression of a cancer causing protein, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH. [00511] The compound of paragraph [00505] or paragraph [00507], wherein the sub-series of three consecutive side chains is bound to a sub-series of the chain of atoms comprising a first atom that is bound to a second atom, a third atom that is bound to the second atom, a fourth atom that is bound to the third atom, a fifth atom that is bound to the fourth atom, a sixth atom that is bound to the fifth atom, and a seventh atom that is bound to the sixth atom.
[00512] The compound of any one of paragraphs [00505], [00507], and [00511], wherein each of the fifth atom and the sixth atom is not bound to any of guanidinoalkyl and C(O)-alkyl. [00513] The compound of any one of paragraphs [00505], [00507], and [00511], wherein each of the second atom, the fifth atom, and the sixth atom is not bound to any of guanidinoalkyl and C(O)-alkyl.
[00514] The compound of any one of paragraphs [00505], [00507], and [00511], wherein each of the first atom, the second atom, the fifth atom, and the sixth atom is not bound to any of guanidinoalkyl and C(O)-alkyl.
[00515] The compound of any one of paragraphs [00505], [00507], and [00511], wherein each of the first atom, the fourth atom, the fifth atom, and the sixth atom is not bound to any of guanidinoalkyl and C(O)-alkyl. [00516] The compound of any one of paragraphs [00505], [00507], and [00511], wherein each of the second atom, the fourth atom, the fifth atom, and the sixth atom is not bound to any of guanidinoalkyl and C(O)-alkyl.
[00517] The compound of any one of paragraphs [00505], [00507], and [00511]-[00514], wherein the fourth atom is bound to one guanidinoalkyl of the sub-series of three consecutive side chains.
[00518] The compound of any one of paragraphs [00505], [00507], [00511]-[00513], and [00515], wherein the second atom is bound to one guanidinoalkyl of the sub-series of three consecutive side chains.
[00519] The compound of any one of paragraphs [00505], [00507], [00511]-[00513], and [00516], wherein the first atom is bound to one guanidinoalkyl of the sub-series of three consecutive side chains.
[00520] The compound of any one of paragraphs [00505], [00507], [00511]-[00513], [00516], and [00519], Wherein the seventh atom is bound to one guanidinoalkyl of the sub-series of three consecutive side chains.
[00521] The compound of any one of paragraphs [00505], [00507], and [00511]-[00520], wherein the third atom is bound the C(O)-alkyl of the sub-series of three consecutive side chains.
[00522] The compound of paragraph [00511] or paragraph [00512], wherein the sub-series of the chain of atoms further comprises a eighth atom that is bound to the seventh atom, a ninth atom that is bound to the eighth atom, a tenth atom that is bound to the ninth atom, an eleventh atom that is bound to the tenth atom, and a twelfth atom that is bound to the eleventh atom. [00523] The compound of paragraph [00522], wherein each of the eleventh atom and the twelfth atom is not bound to any of guanidinoalkyl and C(O)-alkyl.
[00524] The compound of paragraph [00522], wherein each of the eighth atom, the eleventh atom, and the twelfth atom is not bound to any of guanidinoalkyl and C(0)-alkyl.
[00525] The compound of paragraph [00522], wherein each of the seventh atom, the eighth atom, the eleventh atom, and the twelfth atom is not bound to any of guanidinoalkyl and C(O)- alkyl.
[00526] The compound of any one of paragraphs [00522]-[00525], wherein the tenth atom is bound to guanidinoalkyl.
[00527] The compound of paragraph [00522], wherein each of the seventh atom, the tenth atom, the eleventh atom, and the twelfth atom is not bound to any of guanidinoalkyl and C(O)-alkyl. [00528] The compound of any one of paragraphs [00522], [00523], and [00527], wherein the eighth atom is bound to guanidinoalkyl. [00529] The compound of paragraph [00522], wherein each of the eighth atom, the tenth atom, the eleventh atom, and the twelfth atom is not bound to any of guani dinoalkyl and C(O)-alkyl. [00530] The compound of any one of paragraphs [00522]-[00529], wherein the ninth atom is bound to C(O)-alkyl.
[00531] The compound of any one of paragraphs [00522]-[00530], wherein the first through twelfth atoms of the sub-series of the chain of atoms together form a repeating unit of a polymer backbone.
[00532] The compound of paragraph [00531], wherein the polymer backbone is a peptide nucleic acid backbone.
[00533] The compound of paragraph [00506] or paragraph [00508], wherein the chain of atoms comprises a first atom that is bound to a second atom, a third atom that is bound to the second atom, a fourth atom that is bound to the third atom, a fifth atom that is bound to the fourth atom, a sixth atom that is bound to the fifth atom, a seventh atom that is bound to the sixth atom, an eighth atom that is bound to the seventh atom, a ninth atom that is bound to the eighth atom, a tenth atom that is bound to the ninth atom, an eleventh atom that is bound to the tenth atom, and a twelfth atom that is bound to the eleventh atom.
[00534] The compound of paragraph [00533], wherein each of the third atom, the fifth atom, the sixth atom, the ninth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00535] The compound of paragraph [00533], wherein each of the second atom, the third atom, the fifth atom, the sixth atom, the eighth atom, the ninth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00536] The compound of paragraph [00533], wherein each of the first atom, the second atom, the third atom, the fifth atom, the sixth atom, the seventh atom, the eighth atom, the ninth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00537] The compound of any one of paragraphs [00533]-[00536], wherein the fourth atom is bound to guanidinoalkyl.
[00538] The compound of any one of paragraphs [00533]-[00536], wherein the tenth atom is bound to guanidinoalkyl.
[00539] The compound of paragraph [00533], wherein each of the second atom, the third atom, the fourth atom, the fifth atom, the sixth atom, the eighth atom, the ninth atom, the tenth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00540] The compound of any one of paragraphs [00533]-[00535], and [00539], wherein the first atom is bound to guanidinoalkyl.
[00541] The compound of any one of paragraphs [00533]-[00535], [00539], and [00540], wherein the seventh atom is bound to guanidinoalkyl.
[00542] The compound of paragraph [00533], wherein each of the first atom, the third atom, the fourth atom, the fifth atom, the sixth atom, the seventh atom, the ninth atom, the tenth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00543] The compound of paragraph [00533] or paragraph [00542], wherein the second atom is bound to guanidinoalkyl.
[00544] The compound of any one of paragraphs [00533], [00542], and [00543], wherein the eighth atom is bound to guanidinoalkyl.
[00545] The compound of any one of paragraphs [00533]-[00544], wherein the third atom is bound to a C(O)-alkyl group.
[00546] The compound of any one of paragraphs [00533]-[00545], wherein the ninth atom is bound to a C(O)-alkyl group.
[00547] The compound of any one of paragraphs [00533]-[00546], wherein the first through twelfth atoms together form a repeating unit of a polymer backbone.
[00548] The compound of paragraph [00547], wherein the polymer backbone is a peptide nucleic acid backbone.
[00549] The compound of paragraph [00509] or paragraph [00510], wherein the chain of atoms comprises a first atom that is bound to a second atom, a third atom that is bound to the second atom, a fourth atom that is bound to the third atom, a fifth atom that is bound to the fourth atom, and a sixth atom that is bound to the fifth atom, wherein the first atom is bound to a side chain of the series of side chains, and each of the second atom, the third atom, the fourth atom, the fifth atom, and the sixth atom is not bound to a side chain of the series of side chains.
[00550] The compound of paragraph [00549], wherein the third atom is bound to a C(O)-alkyl group.
[00551] The compound of paragraph [00549], wherein the second atom is bound to a C(O)-alkyl group.
[00552] The compound of paragraph [00549], wherein the sixth atom is bound to a C(O)-alkyl group.
[00553] The compound of any one of paragraphs [00549]-[00552], wherein the first through sixth atoms together form a repeating unit of a polymer backbone.
[00554] The compound of paragraph [00553], wherein the polymer backbone is a peptide nucleic acid backbone.
[00555] The compound of any one of paragraphs [00509], [00510], and [00549]-[00554], wherein each of the side chains is independently aminoalkyl, guanidinoalkyl, ureidolalkyl, ami dinoalkyl, morpholinoalkyl, piperidinylalkyl, piperazinylalkyl, or pyrrolidinylalkyl. [00556] The compound of any one of paragraphs [00509], [00510], and [00549]-[00554], wherein each of the side chains is independently aminoalkyl or guani dinoalkyl.
[00557] The compound of any one of paragraphs [00509], [00510], and [00549]-[00554], wherein each of the side chains is independently guanidinoalkyl.
[00558] The compound of any one of paragraphs [00505]-[00508], [00511]-[00548], and [00555]-[00557], wherein each guanidinoalkyl is independently H, 3 -guani dinoprop- 1-yl, or 4- guani dinobut- 1 -y 1.
[00559] The compound of any one of paragraphs [00505]-[00508], [00511]-[00548], and [00555]-[00557], wherein each guanidinoalkyl is 3-guanidinoprop-l-yl.
[00560] The compound of any one of paragraphs [00505]-[00508], [00511]-[00548], and [00555]-[00557], wherein each guanidinoalkyl is 4-guanidinobut-l-yl.
[00561] The compound of any one of paragraphs [00505], [00507], [00511]-[00521 ], [00523], [00525], [00527], [00529], [00530], [00545], [00546], [00550], [00551], and [00552], wherein each C(O)-alkyl group is independently acetyl.
[00562] The compound of any one of paragraphs [00505], [00506], and [00510], wherein the cancer causing protein is mutant K-ras.
[00563] The compound of any one of paragraphs [00505], [00506], and [00510], wherein the cancer causing protein is G12D K-ras.
[00564] The compound of any one of paragraphs [00505], [00506], and [00510], wherein the cancer causing protein is G12C K-ras.
[00565] The compound of any one of paragraphs [00505], [00506], and [00510], wherein the cancer causing protein is G12V K-ras.
[00566] The compound of any one of paragraphs [00505], [00506], and [00510], wherein the compound binds to a sequence of nucleic acids encoding a KRAS gene.
[00567] The compound of any one of paragraphs [00505], [00506], and [00510], wherein the compound binds to a sequence of nucleic acids encoding non-wild type KRAS.
[00568] The compound of any one of paragraphs [00505], [00506], and [00510], wherein the compound binds to a sequence of nucleic acids encoding G12D KRAS.
[00569] The compound of any one of paragraphs [00505], [00506], and [00510], wherein the compound binds to a sequence of nucleic acids encoding G12C KRAS.
[00570] The compound of any one of paragraphs [00505], [00506], and [00510], wherein the compound binds to a sequence of nucleic acids encoding G12V KRAS.
[00571] The compound of any one of paragraphs [00507], [00508], [00509], and [00566]- [00570], wherein the sequence of nucleic acids is a DNA sequence.
[00572] The compound of any one of paragraphs [00507], [00508], [00509], and [00566]- [00570], wherein the sequence of nucleic acids is an mRNA sequence.
[00573] The compound of any one of paragraphs [00505]-[00572], wherein the structure is a oligonucleotide or oligonucleotide analogue.
[00574] The compound of any one of paragraphs [00505]-[00572], wherein the structure is a peptide nucleic acid.
[00575] A compound comprising a structure that is:
N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1-ξ C-Terminus wherein:
N-Terminus is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent;
C-Terminus is OH, O-alkyl, a peptide sequence, or ML·;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
Z is a peptide nucleic acid sequence;
PNA2 is a peptide nucleic acid sequence or absent;
L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent;
L6 is a linker group or absent; and or a pharmaceutically-acceptable salt or ionized form thereof.
[00576] The compound of paragraph [00575], wherein Z is a peptide nucleic acid sequence according to PNA SEQ NO 1, PNA SEQ NO 2, PNA SEQ NO 3, PNA SEQ NO 4, PNA SEQ NO 5, PNA SEQ NO 6, PNA SEQ NO 7, PNA SEQ NO 8, PNA SEQ NO 9, PNA SEQ NO 10, PNA SEQ NO 11, PNA SEQ NO 12, PNA SEQ NO 13, PNA SEQ NO 14, PNA SEQ NO 15,
PNA SEQ NO 16, PNA SEQ NO 17, PNA SEQ NO 18, PNA SEQ NO 19, PNA SEQ NO 20,
PNA SEQ NO 21, PNA SEQ NO 22, PNA SEQ NO 23, PNA SEQ NO 24, PNA SEQ NO 25,
PNA SEQ NO 26, PNA SEQ NO 27, PNA SEQ NO 28, PNA SEQ NO 29, PNA SEQ NO 30,
PNA SEQ NO 31, PNA SEQ NO 32, PNA SEQ NO 33, PNA SEQ NO 34, PNA SEQ NO 35, PNA SEQ NO 36, PNA SEQ NO 37, PNA SEQ NO 38, PNA SEQ NO 39, PNA SEQ NO 40, PNA SEQ NO 41, PNA SEQ NO 42, PNA SEQ NO 43, PNA SEQ NO 44, PNA SEQ NO 45, PNA SEQ NO 46, PNA SEQ NO 47, PNA SEQ NO 48, PNA SEQ NO 49, PNA SEQ NO 50, PNA SEQ NO 51, PNA SEQ NO 52, PNA SEQ NO 53, PNA SEQ NO 54, PNA SEQ NO 55, PNA SEQ NO 56, PNA SEQ NO 57, PNA SEQ NO 58, PNA SEQ NO 59, PNA SEQ NO 60, PNA SEQ NO 61, PNA SEQ NO 62, PNA SEQ NO 63, PNA SEQ NO 64, PNA SEQ NO 65, PNA SEQ NO 66, PNA SEQ NO 67, PNA SEQ NO 68, PNA SEQ NO 69, PNA SEQ NO 70, PNA SEQ NO 71, PNA SEQ NO 72, PNA SEQ NO 73, PNA SEQ NO 74, PNA SEQ NO 75, PNA SEQ NO 76, PNA SEQ NO 77, PNA SEQ NO 78, PNA SEQ NO 79, PNA SEQ NO 80, PNA SEQ NO 81, PNA SEQ NO 82, PNA SEQ NO 83, PNA SEQ NO 84, PNA SEQ NO 85, PNA SEQ NO 86, PNA SEQ NO 87, PNA SEQ NO 88, PNA SEQ NO 89, PNA SEQ NO 90, PNA SEQ NO 91, PNA SEQ NO 92, PNA SEQ NO 93, PNA SEQ NO 94, PNA SEQ NO 95, PNA SEQ NO 96, PNA SEQ NO 97, PNA SEQ NO 98, PNA SEQ NO 99, PNA SEQ NO 100, PNA SEQ NO 101, PNA SEQ NO 102, PNA SEQ NO 103, PNA SEQ NO 104, PNA SEQ NO 105, PNA SEQ NO 106, PNA SEQ NO 107, PNA SEQ NO 108, PNA SEQ NO 109, PNA SEQ NO 110, PNA SEQ NO 111, PNA SEQ NO 112, PNA SEQ NO 113, PNA SEQ NO 114, PNA SEQ NO 115, PNA SEQ NO 116, PNA SEQ NO 117, PNA SEQ NO 118, PNA SEQ NO 119, PNA SEQ NO 120, PNA SEQ NO 121, PNA SEQ NO 122, PNA SEQ NO 123, PNA SEQ NO 124, PNA SEQ NO 125, PNA SEQ NO 126, PNA SEQ NO 127, PNA SEQ NO 128, PNA SEQ NO 129, PNA SEQ NO 130, PNA SEQ NO 131, PNA SEQ NO 132, PNA SEQ NO 133, PNA SEQ NO 134, PNA SEQ NO 135, PNA SEQ NO 136, PNA SEQ NO 137, PNA SEQ NO 138, PNA SEQ NO 139, PNA SEQ NO 140, PNA SEQ NO 141, PNA SEQ NO 142, PNA SEQ NO 143, PNA SEQ NO 144, PNA SEQ NO 145, PNA SEQ NO 146, PNA SEQ NO 147, PNA SEQ NO 148, PNA SEQ NO 149, PNA SEQ NO 150, PNA SEQ NO 151, PNA SEQ NO 152, PNA SEQ NO 153, PNA SEQ NO 154, PNA SEQ NO 155, PNA SEQ NO 156, PNA SEQ NO 157, PNA SEQ NO 158, PNA SEQ NO 159, PNA SEQ NO 160, PNA SEQ NO 161, PNA SEQ NO 162, PNA SEQ NO 163, PNA SEQ NO 164, PNA SEQ NO 165, PNA SEQ NO 166, PNA SEQ NO 167, or PNA SEQ NO 168.
[00577] The compound of paragraph [00575], wherein Z is a peptide nucleic acid sequence according to PNA SEQ NO 1, PNA SEQ NO 2, PNA SEQ NO 3, PNA SEQ NO 4, PNA SEQ NO 5, PNA SEQ NO 6, PNA SEQ NO 7, PNA SEQ NO 8, PNA SEQ NO 9, PNA SEQ NO 10, PNA SEQ NO 11, PNA SEQ NO 12, PNA SEQ NO 13, PNA SEQ NO 14, PNA SEQ NO 15, PNA SEQ NO 16, PNA SEQ NO 17, PNA SEQ NO 18, PNA SEQ NO 19, PNA SEQ NO 20, PNA SEQ NO 21, PNA SEQ NO 22, PNA SEQ NO 23, PNA SEQ NO 24, PNA SEQ NO 25, PNA SEQ NO 26, PNA SEQ NO 27, PNA SEQ NO 28, PNA SEQ NO 29, PNA SEQ NO 30, PNA SEQ NO 31, PNA SEQ NO 32, PNA SEQ NO 33, PNA SEQ NO 34, PNA SEQ NO 35, PNA SEQ NO 36, PNA SEQ NO 37, PNA SEQ NO 38, PNA SEQ NO 39, PNA SEQ NO 40, PNA SEQ NO 60, PNA SEQ NO 61, PNA SEQ NO 62, PNA SEQ NO 63, PNA SEQ NO 64, PNA SEQ NO 65, PNA SEQ NO 83, PNA SEQ NO 84, PNA SEQ NO 85, PNA SEQ NO 86, PNA SEQ NO 87, PNA SEQ NO 88, PNA SEQ NO 89, PNA SEQ NO 90, PNA SEQ NO 91, PNA SEQ NO 107, PNA SEQ NO 108, PNA SEQ NO 109, PNA SEQ NO 110, PNA SEQ NO 111, PNA SEQ NO 112, PNA SEQ NO 113, PNA SEQ NO 114, PNA SEQ NO 115, PNA SEQ NO 116, PNA SEQ NO 117, PNA SEQ NO 118, PNA SEQ NO 119, PNA SEQ NO 120, PNA SEQ NO 121, PNA SEQ NO 122, PNA SEQ NO 123, PNA SEQ NO 124, PNA SEQ NO 125, PNA SEQ NO 126, PNA SEQ NO 127, PNA SEQ NO 128, PNA SEQ NO 129, PNA SEQ NO 130, PNA SEQ NO 131, PNA SEQ NO 132, PNA SEQ NO 133, PNA SEQ NO 134, PNA SEQ NO 135, PNA SEQ NO 136, PNA SEQ NO 137, PNA SEQ NO 138, PNA SEQ NO 139, PNA SEQ NO 140, PNA SEQ NO 141, PNA SEQ NO 142, PNA SEQ NO 143, PNA SEQ NO 144, PNA SEQ NO 145, PNA SEQ NO 146, PNA SEQ NO 147, PNA SEQ NO 148, or PNA SEQ NO 149.
[00578] A compound comprising a structure that is:
Figure imgf000244_0001
wherein: the first number of units with variables defined independently is at least zero; the second number of units with variables defined independently is at least 3; the third number of units with variables defined independently is at least zero;
A-Terminus is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R3 is independently alkyl that is unsubstituted or substituted or H; each R4 is independently R2; each R5 is independently alkyl that is unsubstituted or substituted or H; each R6 is independently R2; each R7 is independently alkyl that is unsubstituted or substituted or H; each R8 is independently R2, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; each Ralpha1 is independently alkyl that is unsubstituted or substituted or H; each Ralpha2 is independently alkyl that is unsubstituted or substituted or H; each Ralpha3 is independently alkyl that is unsubstituted or substituted or H; each Ralpha4 is independently alkyl that is unsubstituted or substituted or H;
C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent;
L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof [00579] The compound of paragraph [00578], wherein the first number of units with variables defined independently is 3-1,000.
[00580] The compound of paragraph [00578], wherein the first number of units with variables defined independently is 3-100.
[00581] The compound of paragraph [00578], wherein the first number of units with variables defined independently is 3-50. [00582] The compound of paragraph [00578], wherein the first number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30
[00583] The compound of paragraph [00578], wherein the first number of units with variables defined independently is zero.
[00584] The compound of paragraph [00578], wherein the first number of units with variables defined independently is at least 11.
[00585] The compound of paragraph [00578], wherein the first number of units with variables defined independently is 11-1,000.
[00586] The compound of paragraph [00578], wherein the first number of units with variables defined independently is 11-100.
[00587] The compound of paragraph [00578], wherein the first number of units with variables defined independently is 11-50.
[00588] The compound of paragraph [00578], wherein the first number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[00589] The compound of any one of paragraphs [00578]-[00588], wherein the second number of units with variables defined independently is 3-1,000.
[00590] The compound of any one of paragraphs [00578]-[00588], wherein the second number of units with variables defined independently is 3-100.
[00591] The compound of any one of paragraphs [00578]-[00588], wherein the second number of units with variables defined independently is 3-50.
[00592] The compound of any one of paragraphs [00578]-[00588], wherein the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[00593] The compound of any one of paragraphs [00578]-[00588], wherein the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[00594] The compound of any one of paragraphs [00578]-[00588], wherein the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, or 10.
[00595] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is 3-1,000.
[00596] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is 3-100.
[00597] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is 3-50.
[00598] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[00599] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is zero.
[00600] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is at least 11.
[00601] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is 11-1,000.
[00602] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is 11-100.
[00603] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is 11-50.
[00604] The compound of any one of paragraphs [00578]-[00594], wherein the third number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, or 30.
[00605] The compound of any one of paragraphs [00578]-[00604], wherein each Ralpha1 is H. [00606] The compound of any one of paragraphs [00578]-[00604], wherein each Ralpha1 is independently alkyl that is unsubstituted.
[00607] The compound of paragraph [00606], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-1-yl, prop-2-yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00608] The compound of paragraph [00606], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-1-yl, orbut-2-yl.
[00609] The compound of any one of paragraphs [00578]-[00604], wherein each Ralpha1 is independently alkyl that is substituted.
[00610] The compound of paragraph [00609], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N-methylguanidino group, or an amido group.
[00611] The compound of paragraph [00609], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H -imidazol-4-ylmethyl, 1 -H -indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl. [00612] The compound of any one of paragraphs [00578]-[00604], wherein each Ralpha1 is independently a guanidinoalkyl group or a hydroxyalkyl group.
[00613] The compound of any one of paragraphs [00578]-[00604], wherein each Ralpha1 is hydroxymethyl.
[00614] The compound of any one of paragraphs [00578]-[00604], wherein each Ralpha1 is independently H, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl.
[00615] The compound of any one of paragraphs [00578]-[00604], wherein at least one iteration of Ralpha1 is 3-guanidinoprop-1-yl.
[00616] The compound of any one of paragraphs [00578]-[00604], wherein at least a third of the iterations of Ralpha1 are 3-guanidinoprop-1-yl.
[00617] The compound of any one of paragraphs [00578]-[00604], wherein at least half the iterations of Ralpha1 are 3-guanidinoprop- 1yl.
[00618] The compound of any one of paragraphs [00578]-[00617], wherein each Ralpha4 is H. [00619] The compound of any one of paragraphs [00578]-[00617], wherein each Ralpha4 is independently alkyl that is unsubstituted.
[00620] The compound of paragraph [00619], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-1-yl, prop-2-yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00621] The compound of paragraph [00619], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-1-yl, orbut-2-yl.
[00622] The compound of any one of paragraphs [00578]-[00617], wherein each Ralpha4 is independently alkyl that is substituted.
[00623] The compound of paragraph [00622], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N-methylguanidino group, or an amido group.
[00624] The compound of paragraph [00622], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-1-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-1-yl, 3-aminoprop-1-yl, 1 -H -imidazol-ylmethyl, 1 -H -indol-3-ylmethyl, benzyl, 4- hydroxyphen-1-ylmethyl, 2-carboxylatoeth-1-yl, 3-carboxylatoprop-1-yl, 3-guanidinoprop-1-yl, 4-guanidinobut-1-yl, 2-carbamoyleth-1-yl, or 3-carbamoylprop-1-yl.
[00625] The compound of any one of paragraphs [00578]-[00617], wherein each Ralpha4 is independently a guanidinoalkyl group or a hydroxyalkyl group.
[00626] The compound of any one of paragraphs [00578]-[00617], wherein each Ralpha4 is hydroxymethyl.
[00627] The compound of any one of paragraphs [00578]-[00617], wherein each Ralpha4 is independently H, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl.
[00628] The compound of any one of paragraphs [00578]-[00617], wherein at least one iteration of Ralpha4 3 -guanidinoprop- 1 -yl .
[00629] The compound of any one of paragraphs [00578]-[00617], wherein at least a third of the iterations of Ralpha4 are 3-guanidinoprop-1-yl.
[00630] The compound of any one of paragraphs [00578]-[00617], wherein at least half the iterations of Ralpha4 are 3-guanidinoprop-1-yl.
[00631] The compound of any one of paragraphs [00578]-[00630], wherein each R1 is independently alkyl that is unsubstituted.
[00632] The compound of paragraph [00631], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-1-yl, prop-2-yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00633] The compound of paragraph [00631], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
[00634] The compound of any one of paragraphs [00578]-[00630], wherein each R1 is independently alkyl that is substituted.
[00635] The compound of paragraph [00634], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N-methylguanidino group, or an amido group.
[00636] The compound of paragraph [00634], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-1-yl, sulfhydrylmethyl, 2-thiomethyleth-1-yl, 4- aminobut-1-yl, 3-aminoprop-1-yl, 1 -H -imidazol-ylmethyl, 1 -H -indol-3-ylmethyl, benzyl, 4- hydroxyphen-1-ylmethyl, 2-carboxylatoeth-1-yl, 3-carboxylatoprop-1-yl, 3-guanidinoprop-1-yl, 4-guanidinobut-1-yl, 2-carbamoyleth-1-yl, or 3-carbamoylprop-1-yl.
[00637] The compound of any one of paragraphs [00578]-[00630], wherein each R1 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
[00638] The compound of any one of paragraphs [00578]-[00630] and [00634]-[00637], wherein at least one iteration of R1 is a hydroxyalkyl group.
[00639] The compound of any one of paragraphs [00578]-[00630] and [00634]-[00637], wherein at least one iteration of R1 is hydroxylmethyl.
[00640] The compound of any one of paragraphs [00578]-[00630] and [00634]-[00637], wherein at least a third of the iterations of R1 are hydroxylmethyl.
[00641] The compound of any one of paragraphs [00578]-[00630] and [00634]-[00637], wherein at least half the iterations of R1 are hydroxylmethyl.
[00642] The compound of any one of paragraphs [00578]-[00641], wherein each R7 is independently alkyl that is unsubstituted.
[00643] The compound of paragraph [00642], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-1-yl, prop-2-yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00644] The compound of paragraph [00642], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-1-yl, orbut-2-yl.
[00645] The compound of any one of paragraphs [00578]-[00641], wherein each R7 is independently alkyl that is substituted.
[00646] The compound of paragraph [00645], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N-methylguanidino group, or an amido group.
[00647] The compound of paragraph [00645], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-1-yl, sulfhydrylmethyl, 2-thiomethyleth-1-yl, 4- aminobut-1-yl, 3-aminoprop-1-yl, 1 -H -imidazol-ylmethyl, 1 -H -indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-1-yl.
[00648] The compound of any one of paragraphs [00578]-[00641], wherein each R7 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
[00649] The compound of any one of paragraphs [00578]-[00641] and [00645]-[00647], wherein at least one iteration of R7 is a hydroxyalkyl group.
[00650] The compound of any one of paragraphs [00578]-[00641] and [00645]-[00647], wherein at least one iteration of R7 is hydroxylmethyl.
[00651] The compound of any one of paragraphs [00578]-[00641] and [00645]-[00647], wherein at least a third of the iterations of R7 are hydroxylmethyl.
[00652] The compound of any one of paragraphs [00578]-[00641] and [00645]-[00647], wherein at least half the iterations of R7 are hydroxylmethyl.
[00653] The compound of any one of paragraphs [00578]-[00652], wherein each R3 is independently an alkyl group that is unsubstituted or substituted, and each R5 is independently a group that is not substituted alkyl.
[00654] The compound of any one of paragraphs [00578]-[00652], wherein each R3 is independently a guanidinoalkyl group, and each R5 is independently a group that is not guanidinoalkyl.
[00655] The compound of any one of paragraphs [00578]-[00652], wherein each R3 is independently a hydroxyalkyl group, and each R5 is independently a group that is not hydroxyalkyl. [00656] The compound of any one of paragraphs [00578]-[00655], wherein each R3 is hydroxymethyl.
[00657] The compound of any one of paragraphs [00578]-[00656], wherein each R5 is H. [00658] The compound of any one of paragraphs [00578]-[00657], wherein each Ralpha2 and each Ralpha3 is H.
[00659] The compound of any one of paragraphs [00578]-[00652], wherein each Ralpha2 is independently an alkyl group that is unsubstituted or substituted, and Ralpha3 is independently a group that is not substituted alkyl.
[00660] The compound of any one of paragraphs [00578]-[00652], wherein each Ralpha2 is independently a guanidinoalkyl group, and each Ralpha3 is independently a group that is not guanidinoalkyl.
[00661] The compound of any one of paragraphs [00578]-[00652], wherein each Ralpha2 is independently a hydroxyalkyl group, and each Ralpha3 is independently a group that is not hydroxy alkyl.
[00662] The compound of any one of paragraphs [00659]-[00661], wherein each Ralpha2 is hydroxymethyl.
[00663] The compound of any one of paragraphs [00659]-[00662], wherein each Ralpha3 is H. [00664] The compound of any one of paragraphs [00659]-[00663], wherein each R3 and each R5 is H.
[00665] A compound comprising a structure that is:
N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1-ξ-
Figure imgf000251_0001
wherein: the number of units with variables defined independently is at least 3;
.A-Terminus is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each Ralpha ys independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle;
C-Terminus is OH, O-alkyl, a peptide sequence, or NH2
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent;
L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[00666] The compound of paragraph [00665], wherein the number of units with variables defined independently is at least 11.
[00667] The compound of paragraph [00665], wherein the number of units with variables defined independently is 11-1,000.
[00668] The compound of paragraph [00665], wherein the number of units with variables defined independently is 11-100.
[00669] The compound of paragraph [00665], wherein the number of units with variables defined independently is 11-50.
[00670] The compound of paragraph [00665], wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[00671] The compound of any one of paragraphs [00665]-[00670], wherein each Ralpha is H. [00672] The compound of any one of paragraphs [00665]-[00670], wherein each Ralpha is independently alkyl that is unsubstituted.
[00673] The compound of paragraph [00671], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-1-yl, prop-2-yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00674] The compound of paragraph [00671], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-1-yl, orbut-2-yl.
[00675] The compound of any one of paragraphs [00665]-[00670], wherein each Ralpha is independently alkyl that is substituted.
[00676] The compound of paragraph [00675], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N-methylguanidino group, or an amido group.
[00677] The compound of paragraph [00675], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-1-yl, sulfhydrylmethyl, 2-thiomethyleth-1-yl, 4- aminobut-1-yl, 3-aminoprop-1-yl, 1 -H -imidazo l-4-ylmethyl, 1 -H -indol-3-ylmethyl, benzyl, 4- hydroxyphen-1-ylmethyl, 2-carboxylatoeth-1-yl, 3-carboxylatoprop-1-yl, 3-guanidinoprop-1-yl, 4-guanidinobut-1-yl, 2-carbamoyleth-1-yl, or 3-carbamoylprop-1-yl.
[00678] The compound of any one of paragraphs [00665]-[00670], wherein each Ralpha is independently H, 3-guanidinoprop-1-yl, or 4-guanidinobut-1-yl.
[00679] The compound of paragraph [00678], wherein at least one iteration of Ralpha is 3- guani dinoprop- 1 -yl .
[00680] The compound of paragraph [00678], wherein at least a third of the iterations of Ralpha are 3-guanidinoprop-1-yl.
[00681] The compound of paragraph [00678], wherein at least half the iterations of Ralpha are 3- guani dinoprop- 1 -yl .
[00682] The compound of any one of paragraphs [00665]-[00681], wherein the number of units with variables defined independently is at least 11; and at least one iteration of R1 is a hydroxy alkyl group.
[00683] The compound of any one of paragraphs [00665]-[00682], wherein the number of units with variables defined independently is 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000253_0001
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000253_0002
a third unit is present, and in the third unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000254_0001
a fourth unit is present, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000254_0002
a fifth unit is present, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000254_0003
a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000254_0004
a seventh unit is present, and in the seventh unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000254_0005
an eighth unit is present, and in the eighth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000254_0006
Figure imgf000255_0001
a ninth unit is present, and in the ninth unit:
Figure imgf000255_0002
a tenth unit is present, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000255_0003
an eleventh unit is present, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000255_0004
a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000255_0005
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000256_0001
a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000256_0002
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000256_0003
a sixteenth unit is present, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000256_0004
a seventeenth unit is present or absent, and in the seventeenth unit: 1
Figure imgf000256_0005
[00684] The compound of paragraph [00683], wherein of the units with variables defined independently, counting from A'-Tcrminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, and the seventeenth unit, independently if present, each have -CH2OH at R1. [00685] The compound of paragraph [00683], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, and the seventeenth unit, independently if present, each have H at R1.
[00686] The compound of paragraph [00683], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, and the seventeenth unit, independently if present, each have -CH2OH at R1.
[00687] The compound of paragraph [00686], wherein of the units with variables defined independently, counting from N-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, and the sixteenth unit, independently if present, each have H at R1.
[00688] The compound of paragraph [00683], wherein of the units with variables defined independently, counting from N-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, and the sixteenth unit, independently if present, each have -CH2OH at R1.
[00689] The compound of paragraph [00688], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, and the seventeenth unit, independently if present, each have H at R1.
[00690] The compound of any one of paragraphs [00665]-[00682], wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000257_0001
a second unit is present or absent, and in the second unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000258_0001
O a third unit is present or absent, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000258_0002
a fourth unit is present or absent, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-11yl;
Figure imgf000258_0003
a fifth unit is present, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000258_0004
O a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000258_0005
a seventh unit is present, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000258_0006
an eighth unit is present, and in the eighth unit:
Figure imgf000259_0001
a ninth unit is present, and in the ninth unit:
Figure imgf000259_0002
a tenth unit is present, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000259_0003
an eleventh unit is present, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000259_0004
O a twelfth unit is present, and in the twelfth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000260_0001
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000260_0002
a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000260_0003
O a fifteenth unit is present or absent, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000260_0004
a sixteenth unit is present or absent, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000260_0005
a seventeenth unit is present or absent, and in the seventeenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000260_0006
[00691] The compound of paragraph [00690], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, and the seventeenth unit, independently if present, each have -CH2OH at R1. [00692] The compound of paragraph [00690], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, and the seventeenth unit, independently if present, each have H at R1.
[00693] The compound of paragraph [00690], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, and the seventeenth unit, independently if present, each have -CH2OH at R1.
[00694] The compound of paragraph [00693], wherein of the units with variables defined independently, counting from N-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, and the sixteenth unit, independently if present, each have H at R1.
[00695] The compound of paragraph [00690], wherein of the units with variables defined independently, counting from N-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, and the sixteenth unit, independently if present, each have -CH2OH at R1.
[00696] The compound of paragraph [00695], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, and the seventeenth unit, independently if present, each have H at R1.
[00697] The compound of any one of paragraphs [00665]-[00682], wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000261_0001
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000262_0001
a third unit is present or absent, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000262_0002
a fourth unit is present or absent, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000262_0003
a fifth unit is present or absent, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000262_0004
a sixth unit is present or absent, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000262_0005
a seventh unit is present or absent, and in the seventh unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000263_0001
an eighth unit is present or absent, and in the eighth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000263_0002
a ninth unit is present or absent, and in the ninth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000263_0003
a tenth unit is present or absent, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000263_0004
an eleventh unit is present or absent, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000263_0005
a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000263_0006
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000264_0001
a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000264_0002
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000264_0003
O a sixteenth unit is present, and in the sixteenth unit: 1 R2 is
Figure imgf000264_0004
a seventeenth unit is present, and in the seventeenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; R2 is O an eighteenth unit is present, and in the eighteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000265_0001
a nineteenth unit is present, and in the nineteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000265_0002
a twentieth unit is present, and in the twentieth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000265_0003
a twenty-first unit is present, and in the twenty -first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000265_0004
a twenty-second unit is present or absent, and in the twenty-second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000265_0005
a twenty-third unit is present or absent, and in the twenty-third unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000266_0001
a twenty-fourth unit is present or absent, and in the twenty -fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000266_0002
a twenty-fifth unit is present or absent, and in the twenty-fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000266_0003
a twenty-sixth unit is present or absent, and in the twenty-sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000266_0004
R2 is a twenty-seventh unit is present or absent, and in the twenty-seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000266_0005
[00698] The compound of paragraph [00697], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the eighteenth unit, the nineteenth unit, the twentieth unit, the twenty-first unit, the twenty-second unit, the twenty-third unit, the twenty-fourth unit, the twenty-fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have -CH2OH at R1.
[00699] The compound of paragraph [00697], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty-first unit, the twenty -third unit, the twenty- fifth unit, and the twenty-seventh unit, independently if present, each have -CH2OH at R1. [00700] The compound of paragraph [00699], wherein of the units with variables defined independently, counting from N-Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, the sixteenth unit, the eighteenth unit, the twentieth unit, the twenty-second unit, the twenty-fourth unit, and the twenty-sixth unit, independently if present, each have H at R1.
[00701] The compound of paragraph [00697], wherein of the units with variables defined independently, counting from N -Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, the sixteenth unit, the eighteenth unit, the twentieth unit, the twenty-second unit, the twenty-fourth unit, and the twenty-sixth unit, independently if present, each have -CH2OH at R1.
[00702] The compound of paragraph [00701], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty-first unit, the twenty -third unit, the twenty- fifth unit, and the twenty-seventh unit, independently if present, each have H at R1.
[00703] The compound of paragraph [00697], wherein of the units with variables defined independently, counting from N-Terminus the fourth unit, the eighth unit, the twelfth unit, the sixteenth unit, the twentieth unit, and the twenty-fourth unit, independently if present, each have -CH2OH at R1.
[00704] The compound of paragraph [00703], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fifth unit, the sixth unit, the seventh unit, the ninth unit, the tenth unit, the eleventh unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the seventeenth unit, the eighteenth unit, the nineteenth unit, the twenty -first unit, the twenty-second unit, the twenty -third unit, the twenty- fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R1.
[00705] The compound of paragraph [00697], wherein of the units with variables defined independently, counting from N-Terminus, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the eighteenth unit, and the nineteenth unit, independently if present, each have -CH2OH at R1.
[00706] The compound of paragraph [00705], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the twentieth unit, the twenty -first unit, the twenty- second unit, the twenty -third unit, the twenty-fourth unit, the twenty -fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R1.
[00707] The compound of paragraph [00697], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the third unit, the fourth unit, the fifth unit, the seventh unit, the eighth unit, the ninth unit, the eleventh unit, the twelfth unit, the thirteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty -first unit, the twenty -third unit, the twenty-fourth unit, the twenty-fifth unit, and the twenty-seventh unit, independently if present, each have -CH2OH at R1.
[00708] The compound of paragraph [00707], wherein of the units with variables defined independently, counting from N-Terminus, the second unit, the sixth unit, the tenth unit, the fourteenth unit, the eighteenth unit, the twenty-second unit, and the twenty-sixth unit, independently if present, each have H at R1.
[00709] The compound of paragraph [00697], wherein of the units with variables defined independently, counting from N-Terminus, the fourth unit, the eighth unit, the twelfth unit, the sixteenth unit, the seventeenth unit, the twentieth unit, and the twenty -fourth unit, independently if present, each have -CH2OH at R1.
[00710] The compound of paragraph [00709], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fifth unit, the sixth unit, the seventh unit, the ninth unit, the tenth unit, the eleventh unit, the thirteenth unit, the fourteenth unit, the fifteenth unit, the eighteenth unit, the nineteenth unit, the twenty- first unit, the twenty-second unit, the twenty-third unit, the twenty-fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R1.
[00711] The compound of paragraph [00697], wherein of the units with variables defined independently, counting from N-Terminus, the thirteenth unit, the fourteenth unit, the fifteenth unit, the sixteenth unit, the seventeenth unit, the eighteenth unit, and the nineteenth unit, independently if present, each have -CH2OH at R1.
[00712] The compound of paragraph [00711], wherein of the units with variables defined independently, counting from N-Terminus, the first unit, the second unit, the third unit, the fourth unit, the fifth unit, the sixth unit, the seventh unit, the eighth unit, the ninth unit, the tenth unit, the eleventh unit, the twelfth unit, the twentieth unit, the twenty -first unit, the twenty- second unit, the twenty-third unit, the twenty-fourth unit, the twenty-fifth unit, the twenty-sixth unit, and the twenty-seventh unit, independently if present, each have H at R1 [00713] The compound of any one of paragraphs [00578]-[00683], wherein at least a third of the R2 groups in the structure are methyl substituted with a heterocycle.
[00714] The compound of any one of paragraphs [00578]-[00683], wherein at least half of the R2 groups in the structure are methyl substituted with a heterocycle.
[00715] The compound of any one of paragraphs [00578]-[00683], wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
[00716] The compound of any one of paragraphs [00578]-[00681], wherein at least one of the heterocycles of the R2 groups is a divalent nucleobase.
[00717] The compound of any one of paragraphs [00578]-[00681], wherein the heterocycles of the R2 groups are divalent nucleobases.
[00718] The compound of any one of paragraphs [00578]-[00715], wherein the heterocycles of the R2 groups are each independently:
Figure imgf000269_0001
[00719] The compound of any one of paragraphs [00578]-[00715], wherein each R2 is independently: methyl,
Figure imgf000269_0002
Figure imgf000270_0001
[00720] The compound of any one of paragraphs [00665]-[00683], wherein of the units with variables defined independently, counting from N-Terminus, the first, third, sixth, ninth, eleventh, thirteenth, sixteenth, nineteenth, and twenty-second units, independently if present, each have 3 -guani dinoprop- 1-yl at Ralpha.
[00721] The compound of any one of paragraphs [00665]-[00681], wherein each R1 is independently alkyl that is unsubstituted.
[00722] The compound of paragraph [00721], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-1-yl, prop-2-yl, 2-methylprop-1-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00723] The compound of paragraph [00721], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-1-yl, orbut-2-yl.
[00724] The compound of any one of paragraphs [00665]-[00681], wherein each R1 is independently alkyl that is substituted.
[00725] The compound of paragraph [00724], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N-methylguanidino group, or an amido group.
[00726] The compound of paragraph [00724], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-1-yl, sulfhydrylmethyl, 2-thiomethyleth-1-yl, 4- aminobut-1-yl, 3-aminoprop-1-yl, 1 -H -imidazo l-4-ylmethyl, 1 - H-indol-3-ylmethyl, benzyl, 4- hydroxyphen-1-ylmethyl, 2-carboxylatoeth-1-yl, 3-carboxylatoprop-1-yl, 3-guani dinoprop- 1-yl, 4-guanidinobut-1-yl, 2-carbamoyleth-1-yl, or 3-carbamoylprop-1-yl.
[00727] The compound of any one of paragraphs [00665]-[00681], wherein each R1 is independently H, hydroxylmethyl, or 4-guanidinobut-1-yl.
[00728] The compound of any one of paragraphs [00665]-[00681], wherein at least one iteration of R1 is a hydroxy alkyl group.
[00729] The compound of any one of paragraphs [00665]-[00681], wherein at least one iteration of R1 is hydroxylmethyl.
[00730] The compound of paragraph [00728], wherein at least a third of the iterations of R1 are hydroxylmethyl.
[00731] The compound of paragraph [00728], wherein at least half the iterations of R1 are hydroxylmethyl.
[00732] The compound of any one of paragraphs [00575]-[00731], wherein PEP1 is absent. [00733] The compound of any one of paragraphs [00575]-[00731], wherein PEP1 is the peptide sequence.
[00734] The compound of any one of paragraphs [00575]-[00731] and [00733], wherein the peptide sequence of PEP1 is a nuclear localization sequence.
[00735] The compound of any one of paragraphs [00575]-[00731] and [00733], wherein at least one of PEP1 and PEP2 is a peptide sequence of at least three amino acid residues.
[00736] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is -Arg-Arg-.
[00737] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ED NO: 1).
[00738] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp- (SEQ ED NO: 2). [00739] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Ala-Lys-Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 77). [00740] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Ala-Ser-Ser-Leu-Asn-Ile-Ala- (SEQ ID NO: 78).
[00741] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Arg-Phe-Gln-Ile-Leu-Tyr-Arg- (SEQ ID NO: 86).
[00742] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is -(D-Arg)-(D-Arg)-(D-Arg)-.
[00743] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Cys'-Arg-Thr-Ile-Gly-Pro-Ser-Val-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 82).
[00744] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Arg-Gly-Arg-Gly-Arg-Gly-Arg-Gly-Arg-Gly-Arg-Gly-Arg- Gly- (SEQ ED NO: 93).
[00745] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Arg-Tyr-Gln-Phe-Leu-Ile-Arg- (SEQ ED NO: 87).
[00746] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Arg-Ile-Gln-Phe-Leu-Ile-Arg- (SEQ ID NO: 88).
[00747] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Arg-Arg-Trp-Trp-Arg-Arg-Trp-Arg-Arg- (SEQ ED NO: 76). [00748] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -Arg-Arg-Trp-Gln-Trp- (SEQ ED NO: 89).
[00749] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is (D-Thr)-( D-His)-(D-Arg)-(D-Pro)-(D)-Pro)-(D)-Met)-( D-Trp)- (D-Ser)-(D-Pro)-( D-Val)-( D-Trp)-(D-Pro-) (SEQ ID NO: 85).
[00750] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -( D-Pro)-( D-Trp)-(D -Val )-( D-Pro)-(D)-Ser)-( D-Trp)-( D- Met)-(D-Pro)-( D-Pro)-( D-Arg)-( D-His)-(D-Thr)- (SEQ ID NO: 83).
[00751] The compound of any one of paragraphs [00575]-[00731], [00733], and [00735], wherein PEP1 is a sequence that is -( D-His)-( D-Arg)-( D-Pro)-( D-Tyr)-( D-Ile)-( D-Ala)-( J-His)- (SEQ ID NO: 84)
[00752] The compound of any one of paragraphs [00575]-[00751], wherein PEP2 is absent. [00753] The compound of any one of paragraphs [00575]-[00751], wherein PEP2 is the peptide sequence.
[00754] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein the peptide sequence of PEP2 is a nuclear localization sequence.
[00755] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1).
[00756] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP1 is a sequence that is -Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp- (SEQ ID NO: 2).
[00757] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is - Arg-Arg-.
[00758] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -Arg-Phe-Gln-Ile-Leu-Tyr-Arg- (SEQ ID NO: 86).
[00759] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is -(D- Arg)-(D-Arg)-(D- Arg)- .
[00760] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -Cys'-Arg-Thr-Ile-Gly-Pro-Ser-Val-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 82).
[00761] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -Arg-Gly-Arg-Gly-Arg-Gly-Arg-Gly-Arg-Gly-Arg-Gly-Arg-Gly- (SEQ ID NO: 93.
[00762] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -Arg-Tyr-Gln-Phe-Leu-Ile-Arg- (SEQ ID NO: 87).
[00763] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -Arg-Ile-Gln-Phe-Leu-Ile-Arg- (SEQ ID NO: 88). [00764] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -Arg-Arg-Trp-Trp-Arg-Arg-Trp-Arg-Arg- (SEQ ID NO: 76).
[00765] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -Arg-Arg-Trp-Gln-Trp- (SEQ ID NO: 89).
[00766] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is (D-Thr)-(D)-His)-(D-Arg)-(D)-Pro)-(D)-Pro)-(D)-Met)-(D-Trp)-(D)-Ser)-(D-Pro)- (D -Val)-(D-Trp)-(D -Pro-) (SEQ ID NO: 85).
[00767] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -(D)-Pro)-(D-Trp)-(D-Val)-(D)-Pro)-(D)-Ser)-(D)-Trp)-(D)-Met)-(D)-Pro)-(D)- Pro)-(D-Arg)-(D-His)-(D-Thr)- (SEQ ID NO: 83).
[00768] The compound of any one of paragraphs [00575]-[00751] or [00753], wherein PEP2 is a sequence that is -(D -His)-(D -Arg)-(D -Pro)-( D-Tyr)-(D -Ile)-(D-Ala)-(D -His)- (SEQ ID NO: 84).
[00769] The compound of any one of paragraphs [00575]-[00768], wherein SOL1 is absent. [00770] The compound of any one of paragraphs [00575]-[00768], wherein SOL1 is the water- solubilizing group.
[00771] The compound of any one of paragraphs [00575]-[00768] and [00770], wherein the water-solubilizing group of SOL1 is a peptide sequence.
[00772] The compound of any one of paragraphs [00575]-[00768], [00770], and [00771], wherein the water-solubilizing group of SOL1 is a group that contains multiple electrical charges at physiological pH.
[00773] The compound of any one of paragraphs [00575]-[00768] and [00770]-[00772], wherein the water-solubilizing group of SOL1 is a group that contains multiple positive charges at physiological pH.
[00774] The compound of any one of paragraphs [00575]-[00768] and [00770], wherein the water-solubilizing group of SOL1 is a polyethyleneglycol group.
[00775] The compound of any one of paragraphs [00575]-[00768] and [00770], wherein the water-solubilizing group of SOL1 is -Arg-Arg-NH(CH2)2C(0)-Arg-Arg-.
[00776] The compound of any one of paragraphs [00575]-[00768] and [00770], wherein the water-solubilizing group of SOL1 is a group of formula: R1a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00777] The compound of any one of paragraphs [00575]-[00768], [00770], and [00776], wherein the water-solubilizing group of SOL1 is a group of formula: wherein p is an integer that is 1-1,000.
[00778] The compound of any one of paragraphs [00575]-[00768] and [00770], wherein the water-solubilizing group of SOL1 is a group of formula:
R1a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00779] The compound of any one of paragraphs [00575]-[00768], [00770], and [00776]- [00778], wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000275_0001
wherein p is an integer that is 1-1,000.
[00780] The compound of any one of paragraphs [00776]-[00779], wherein p is an integer that is 1-100.
[00781] The compound of any one of paragraphs [00776]-[00779], wherein p is an integer that is 1-50.
[00782] The compound of any one of paragraphs [00776]-[00779], wherein p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[00783] The compound of any one of paragraphs [00776]-[00779], wherein p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
[00784] The compound of any one of paragraphs [00776]-[00779], wherein p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10.
[00785] The compound of any one of paragraphs [00776]-[00779], wherein p is an integer that is 5, 6, 7, 8, or 9.
[00786] The compound of any one of paragraphs [00776]-[00779], wherein p is an integer that is 6, 7, or 8.
[00787] The compound of any one of paragraphs [00776]-[00779], wherein p is an integer that is 7.
[00788] The compound of any one of paragraphs [00575]-[00786], wherein SOL2 is absent. [00789] The compound of any one of paragraphs [00575]-[00786], wherein SOL2 is the water- solubilizing group.
[00790] The compound of any one of paragraphs [00575]-[00786] and [00789], wherein the water-solubilizing group of SOL2 is a peptide sequence. [00791] The compound of any one of paragraphs [00575]-[00786], [00789], and [00790], wherein the water-solubilizing group of SOL2 is a group that contains multiple electrical charges at physiological pH.
[00792] The compound of any one of paragraphs [00575]-[00786], and [00789]-[00791], wherein the water-solubilizing group of SOL2 is a group that contains multiple positive charges at physiological pH.
[00793] The compound of any one of paragraphs [00575]-[00786] and [00789], wherein the water-solubilizing group of SOL2 is a polyethyleneglycol group.
[00794] The compound of any one of paragraphs [00575]-[00786] and [00789], wherein the water-solubilizing group of SOL2 is -Arg-Arg-NH(CH2)2C(0)-Arg-Arg-.
[00795] The compound of any one of paragraphs [00575]-[00786] and [00789], wherein the water-solubilizing group of SOL2 is a group of formula:
R1a R iiss2 HHa i,,s aa Ollkk,yy Nll,,H oo,rr N aa( nnaiilttkrrooyggl)ee,nn or aatt Noomm(Pg ppNrroo),ttee wcchttiiennrggei ggnrroo PuugppN;; is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00796] The compound of any one of paragraphs [00575]-[00786], [00789], and [00795], wherein the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000277_0001
wherein p is an integer that is 1-1,000.
[00797] The compound of any one of paragraphs [00575]-[00786] and [00789], wherein the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000277_0002
R1a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00798] The compound of any one of paragraphs [00575]-[00786], [00789], and [00795]- [00797], wherein the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000277_0003
wherein p is an integer that is 1-1,000. [00799] The compound of any one of paragraphs [00795]-[00798], wherein p is an integer that is 1-100.
[00800] The compound of any one of paragraphs [00795]-[00798], wherein p is an integer that is 1-50.
[00801] The compound of any one of paragraphs [00795]-[00798], wherein p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[00802] The compound of any one of paragraphs [00795]-[00798], wherein p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
[00803] The compound of any one of paragraphs [00795]-[00798], wherein p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10.
[00804] The compound of any one of paragraphs [00795]-[00798], wherein p is an integer that is 5, 6, 7, 8, or 9.
[00805] The compound of any one of paragraphs [00795]-[00798], wherein p is an integer that is 6, 7, or 8.
[00806] The compound of any one of paragraphs [00795]-[00798], wherein p is an integer that is 7.
[00807] The compound of any one of paragraphs [00575]-[00806], wherein PNA1 is the peptide nucleic acid sequence.
[00808] The compound of any one of paragraphs [00575]-[00807], wherein PNA2 is the peptide nucleic acid sequence.
[00809] The compound of any one of paragraphs [00575]-[00808], wherein LI is the linker group.
[00810] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is cleavable.
[00811] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is non-cleavable.
[00812] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is a peptide sequence.
[00813] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is a polyamine sequence.
[00814] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is a polyamide sequence.
[00815] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is a residue of an omega-amino fatty acid.
[00816] The compound of any one of paragraphs [00575]-[00809] and [00815], wherein the linker group of L1 is a residue of an omega-amino caproic acid.
[00817] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is a residue of a dicarboxylic acid.
[00818] The compound of any one of paragraphs [00575]-[00809] and [00817], wherein the linker group of L1 is a residue of oxalic acid.
[00819] The compound of any one of paragraphs [00575]-[00809] and [00817], wherein the linker group of L1 is a residue of succinic acid.
[00820] The compound of any one of paragraphs [00575]-[00809], [00812], and [00814], wherein the linker group of L1 is a peptide sequence that is -Glu-Val-Citrulline-.
[00821] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-.
[00822] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(O)-.
[00823] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -Arg-NH(CH2)5C(O)-.
[00824] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NH(CH2)5C(O)-.
[00825] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NH(CH2)2C(O)-Arg-NH(CH2)5C(O)NH(CH2)2C(O)-.
[00826] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L 1 is -NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(OO.
[00827] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -Arg-NH(CH2)5C(0)-Arg-Arg-NH(CH2)2C(O)-Arg-Arg-NH(CH2)5C(O)-.
[00828] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L 1 is -NH(CH2)5C(O)NH(CH2)2-( D-arginine)-( D -arginine)-(D -arginine).
[00829] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NH(CH2CH2O)2CH2C(O)-.
[00830] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NH(CH2CH2O)2CH2C(O)-Arg-.
[00831] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-.
[00832] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-.
[00833] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-Arg-. [00834] The compound of any one of paragraphs [00575]-[00809], wherein the linker group of L1 is -NH(CH2CH2O)2CH2C(O)-Arg-NH(CH2CH2O)2CH2C(O)-Arg-.
[00835] The compound of any one of paragraphs [00575]-[00809], [00812], and [00814], wherein the linker group of L1 is a peptide sequence that is -Lys-.
[00836] The compound of any one of paragraphs [00575]-[00809], [00812], and [00814], wherein the linker group of L1 is a peptide sequence that is -(D-Arg)-(D)-Arg)-(D)-Arg)-. [00837] The compound of any one of paragraphs [00575]-[00836], wherein L2 is the linker group.
[00838] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is cleavable.
[00839] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is non-cleavable.
[00840] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is a peptide sequence.
[00841] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is a polyamine sequence.
[00842] The compound of any one of paragraphs [00575]-[00837] and [00840], wherein the linker group of L2 is a polyamide sequence.
[00843] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is a residue of an omega-amino fatty acid.
[00844] The compound of any one of paragraphs [00575]-[00837] and [00843], wherein the linker group of L2 is a residue of an omega-amino caproic acid.
[00845] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is a residue of a dicarboxylic acid.
[00846] The compound of any one of paragraphs [00575]-[00837] and [00845], wherein the linker group of L2 is a residue of oxalic acid.
[00847] The compound of any one of paragraphs [00575]-[00837] and [00845], wherein the linker group of L2 is a residue of succinic acid.
[00848] The compound of any one of paragraphs [00575]-[00837] and [00840], wherein the linker group of L2 is a peptide sequence that is -Glu-Val- Citrulline-.
[00849] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-.
[00850] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(O)-.
[00851] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -Arg-NH(CH2)5C(O)-.
[00852] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2)5C(O)-.
[00853] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2)2C(O)-Arg-NH(CH2)5C(O)NH(CH2)2C(O)-.
[00854] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00855] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -Arg-NH(CH2)5C(O)-Arg-Arg-NH(CH2)2C(O)-Arg-Arg-NH(CH2)5C(O)-.
[00856] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2)5C(O)NH(CH2)2-(D)-arginine)-( D-arginine)-( D-arginine).
[00857] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2CH2O)2CH2C(O)-.
[00858] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2CH2O)2CH2C(O)-Arg-.
[00859] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-.
[00860] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-.
[00861] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-Arg-.
[00862] The compound of any one of paragraphs [00575]-[00837], wherein the linker group of L2 is -NH(CH2CH2O)2CH2C(O)-Arg-NH(CH2CH2O)2CH2C(O)-Arg-,
[00863] The compound of any one of paragraphs [00575]-[00837] and [00840], wherein the linker group of L2 is a peptide sequence that is -Lys-.
[00864] The compound of any one of paragraphs [00575]-[00837] and [00840], wherein the linker group of L2 is a peptide sequence that is -(D-Arg)-(D-Arg)-(D-Arg)-.
[00865] The compound of any one of paragraphs [00575]-[00864], wherein L3 is the linker group.
[00866] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is cleavable.
[00867] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is non-cleavable.
[00868] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is a peptide sequence. [00869] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is a polyamine sequence.
[00870] The compound of any one of paragraphs [00575]-[00865] and [00868], wherein the linker group of L3 is a polyamide sequence.
[00871] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is a residue of an omega-amino fatty acid.
[00872] The compound of any one of paragraphs [00575]-[00865] and [00871], wherein the linker group of L3 is a residue of an omega-amino caproic acid.
[00873] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is a residue of a dicarboxylic acid.
[00874] The compound of any one of paragraphs [00575]-[00865] and [00873], wherein the linker group of L3 is a residue of oxalic acid.
[00875] The compound of any one of paragraphs [00575]-[00865] and [00873], wherein the linker group of L3 is a residue of succinic acid.
[00876] The compound of any one of paragraphs [00575]-[00865] and [00868], wherein the linker group of L3 is a peptide sequence that is -Glu-Val-Citrulline-.
[00877] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-.
[00878] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(O)-.
[00879] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -Arg-NH(CH2)5C(O)-.
[00880] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2)5C(O)-.
[00881] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2)2C(O)-Arg-NH(CH2)5C(O)NH(CH2)2C(O)-.
[00882] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00883] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -Arg-NH(CH2)5C(O)-Arg-Arg-NH(CH2)2C(O)-Arg-Arg-NH(CH2)5C(O)-.
[00884] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2)5C(O)NH(CH2)2-(D-arginine)-(D-arginine)-(D-arginine).
[00885] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2CH2O)2CH2C(O)-.
[00886] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2CH2O)2CH2C(O)-Arg-.
[00887] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-
[00888] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-.
[00889] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-Arg-.
[00890] The compound of any one of paragraphs [00575]-[00865], wherein the linker group of L3 is -NH(CH2CH2O)2CH2C(O)-Arg-NH(CH2CH2O)2CH2C(O)-Arg-.
[00891] The compound of any one of paragraphs [00575]-[00865] and [00868], wherein the linker group of L3 is a peptide sequence that is -Lys-.
[00892] The compound of any one of paragraphs [00575]-[00865] and [00868], wherein the linker group of L3 is a peptide sequence that is -(D-Arg)-(D-Arg)-(D-Arg)-.
[00893] The compound of any one of paragraphs [00575]-[00892], wherein L4 is the linker group.
[00894] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is cleavable.
[00895] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is non-cleavable.
[00896] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is a peptide sequence.
[00897] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is a polyamine sequence.
[00898] The compound of any one of paragraphs [00575]-[00893] and [00896], wherein the linker group of L4 is a polyamide sequence.
[00899] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is a residue of an omega-amino fatty acid.
[00900] The compound of any one of paragraphs [00575]-[00893] and [00899], wherein the linker group of L4 is a residue of an omega-amino caproic acid.
[00901] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is a residue of a dicarboxylic acid.
[00902] The compound of any one of paragraphs [00575]-[00893] and [00901], wherein the linker group of L4 is a residue of oxalic acid.
[00903] The compound of any one of paragraphs [00575]-[00893] and [00901], wherein the linker group of L4 is a residue of succinic acid. [00904] The compound of any one of paragraphs [00575]-[00893] and [00896], wherein the linker group of L4 is a peptide sequence that is -Glu-Val- Citrulline-.
[00905] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-.
[00906] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(O)-.
[00907] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -Arg-NH(CH2)5C(O)-.
[00908] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2)5C(O)-.
[00909] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2)2C(OO-Arg-NH(CH2)5C(0)NH(CH2)2C(O)-.
[00910] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00911] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -Arg-NH(CH2)5C(O)-Arg-Arg-NH(CH2)2C(O)-Arg-Arg-NH(CH2)5C(O)-.
[00912] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2)5C(0)NH(CH2)2-(D-arginine)-(D-arginine)-(D -arginine).
[00913] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2CH2O)2CH2C(O)-.
[00914] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2CH2O)2CH2C(O)-Arg-.
[00915] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-.
[00916] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-.
[00917] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-Arg-.
[00918] The compound of any one of paragraphs [00575]-[00893], wherein the linker group of L4 is -NH(CH2CH2O)2CH2C(O)-Arg-NH(CH2CH2O)2CH2C(O)-Arg-.
[00919] The compound of any one of paragraphs [00575]-[00893] and [00896], wherein the linker group of L4 is a peptide sequence that is -Lys-
[00920] The compound of any one of paragraphs [00575]-[00893] and [00896], wherein the linker group of L4 is a peptide sequence that is -(D-Arg)-(D-Arg)-(D-Arg)-.
[00921] The compound of any one of paragraphs [00575]-[00920], wherein L5 is the linker group.
[00922] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is cleavable.
[00923] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is non-cleavable.
[00924] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is a peptide sequence.
[00925] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is a polyamine sequence.
[00926] The compound of any one of paragraphs [00575]-[00921] and [00924], wherein the linker group of L5 is a polyamide sequence.
[00927] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is a residue of an omega-amino fatty acid.
[00928] The compound of any one of paragraphs [00575]-[00921], and [00927], wherein the linker group of L5 is a residue of an omega-amino caproic acid.
[00929] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is a residue of a dicarboxylic acid.
[00930] The compound of any one of paragraphs [00575]-[00921] and [00929], wherein the linker group of L5 is a residue of oxalic acid.
[00931] The compound of any one of paragraphs [00575]-[00921] and [00929], wherein the linker group of L5 is a residue of succinic acid.
[00932] The compound of any one of paragraphs [00575]-[00921] and [00924], wherein the linker group of L5 is a peptide sequence that is -Glu-Val-Citrulline-.
[00933] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-.
[00934] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(O)-.
[00935] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -Arg-NH(CH2)5C(O)-.
[00936] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2)5C(O)-.
[00937] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2)2C(O)-Arg-NH(CH2)5C(O)NH(CH2)2C(O)-.
[00938] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O). [00939] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2)5C(O)NH(CH2)2-(D-arginine)-(D-arginine)-(D -arginine).
[00940] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2CH2O)2CH2C(O)-.
[00941] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2CH2O)2CH2C(O)-Arg-.
[00942] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-.
[00943] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-.
[00944] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-Arg-.
[00945] The compound of any one of paragraphs [00575]-[00921], wherein the linker group of L5 is -NH(CH2CH2O)2CH2C(O)-Arg-NH(CH2CH2O)2CH2C(O)-Arg-.
[00946] The compound of any one of paragraphs [00575]-[00921] and [00924], wherein the linker group of L5 is a peptide sequence that is -Lys-.
[00947] The compound of any one of paragraphs [00575]-[00946], wherein L6 is the linker group.
[00948] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is cleavable.
[00949] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is non-cleavable.
[00950] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is a peptide sequence.
[00951] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is a polyamine sequence.
[00952] The compound of any one of paragraphs [00575]-[00947] and [00950], wherein the linker group of L6 is a polyamide sequence.
[00953] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is a residue of an omega-amino fatty acid.
[00954] The compound of any one of paragraphs [00575]-[00947] and [00953], wherein the linker group of L6 is a residue of an omega-amino caproic acid.
[00955] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is a residue of a dicarboxylic acid.
[00956] The compound of any one of paragraphs [00575]-[00947] and [00955], wherein the linker group of L6 is a residue of oxalic acid.
[00957] The compound of any one of paragraphs [00575]-[00947] and [00955], wherein the linker group of L6 is a residue of succinic acid.
[00958] The compound of any one of paragraphs [00575]-[00947] and [00950], wherein the linker group of L6 is a peptide sequence that is -Glu-Val-Citrulline-.
[00959] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(O)-.
[00960] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(O)-.
[00961] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -Arg-NH(CH2)5C(O)-.
[00962] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2)SC(O)-.
[00963] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2)2C(O)-Arg-NH(CH2)5C(O)NH(CH2)2C(O)-.
[00964] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2)5C(O)-Arg-NH(CH2)2C(O)-Arg-NH(CH2)5C(O)-Arg-NH(CH2)2C(O).
[00965] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -Arg-NH(CH2)5C(O)-Arg-Arg-NH(CH2)2C(OO-Arg-Arg-NH(CH2)5C(0)-.
[00966] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2)5C(O)NH(CH2)2-(D -arginine)-(D -arginine)-(D -arginine).
[00967] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2CH2O)2CH2C(O)-.
[00968] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2CH2O)2CH2C(O)-Arg-.
[00969] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-.
[00970] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-.
[00971] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2CH2O)2CH2C(O)-NH(CH2CH2O)2CH2C(O)-Arg-Arg-.
[00972] The compound of any one of paragraphs [00575]-[00947], wherein the linker group of L6 is -NH(CH2CH2O)2CH2C(O)-Arg-NH(CH2CH2O)2CH2C(O)-Arg-.
[00973] The compound of any one of paragraphs [00575]-[00947] and [00950], wherein the linker group of L6 is a peptide sequence that is -Lys- [00974] The compound of any one of paragraphs [00575]-[00947] and [00950], wherein the linker group of L6 is a peptide sequence that is -(D -Arg)-(D -Arg)-(D -Arg)-.
[00975] The compound of any one of paragraphs [00575]-[00683], wherein each of L1, L2, L3, L4, L5, L6, PEP1, PEP1, SOL1, and SOL2 is absent.
[00976] The compound of any one of paragraphs [00665]-[00683], wherein the structure is: N
Figure imgf000288_0002
wherein the number of units with variables defined independently is at least 13; or a pharmaceutically-acceptable salt or ionized form thereof.
[00977] The compound of any one of paragraphs [00665]-[00683] and [00976], wherein the structure is:
Figure imgf000288_0001
or a pharmaceutically-acceptable salt or ionized form thereof.
[00978] The compound of paragraph [00976] or paragraph [00977], wherein at least one iteration of R1 is a hydroxyalkyl group.
[00979] The compound of any one of paragraphs [00575]-[00978], wherein N-Terminus is H. [00980] The compound of any one of paragraphs [00575]-[00978], wherein N-Terminus is acyl. [00981] The compound of any one of paragraphs [00575]-[00978], wherein N-Terminus is the biological agent.
[00982] The compound of paragraph [00981], wherein the biological agent is a vitamin E group. [00983] The compound of paragraph [00981], wherein the biological agent is an O-bound tocopherol group.
[00984] The compound of any one of paragraphs [00575]-[00983], wherein C-Terminus is OH, O-alkyl, or NH2
[00985] The compound of any one of paragraphs [00575]-[00983], wherein C-Terminus is OH, OMe, OEt, Ot-Bu, or NH2
[00986] The compound of any one of paragraphs [00575]-[00983], wherein C-Terminus is NH2 [00987] The compound of any one of paragraphs [00575]-[00983], wherein C-Terminus is the peptide sequence. [00988] The compound of any one of paragraphs [00575]-[00983], wherein C-Terminus is a peptide sequence according to SEQ ID NO: 1, wherein the C-terminal residue of the peptide sequence is amidated.
[00989] A compound comprising a repeating unit of formula:
Figure imgf000289_0001
wherein: each R1 is independently a hydroxyalkyl group, each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R3 is independently a group that is not hydroxyalkyl; each R4 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each Ralpha1 is independently alkyl that is unsubstituted or substituted or H; and each Ralpha2 is independently alkyl that is unsubstituted or substituted or H, wherein the repeating unit occurs at least twice consecutively in the compound.
[00990] The compound of paragraph [00989], wherein each R1 is independently an alkyl group that is unsubstituted or substituted, and each R3 is independently a group that is not substituted alkyl.
[00991] The compound of paragraph [00989], wherein each R1 is independently a guanidinoalkyl group, and each R3 is independently a group that is not guanidinoalkyl.
[00992] The compound of paragraph [00989], wherein each R1 is independently a hydroxyalkyl group, and each R3 is independently a group that is not hydroxyalkyl.
[00993] The compound of any one of paragraphs [00989]-[00992], wherein each R1 is hydroxymethyl.
[00994] The compound of any one of paragraphs [00989]-[00993], wherein each R3 is H. [00995] The compound of any one of paragraphs [00989]-[00994], wherein each Ralpha1 and each Ralpha2 is H.
[00996] The compound of paragraph [00989], wherein each Ralpha1 is independently an alkyl group that is unsubstituted or substituted, and Ralpha2 is independently a group that is not substituted alkyl.
[00997] The compound of paragraph [00989], wherein each Ralpha1 is independently a guanidinoalkyl group, and each Ralpha2 is independently a group that is not guanidinoalkyl. [00998] The compound of paragraph [00989], wherein each Ralpha1 is independently a hydroxyalkyl group, and each Ralpha2 is independently a group that is not hydroxyalkyl. [00999] The compound of any one of paragraphs [00996]-[00998], wherein each Ralpha1 is hydroxymethyl.
[001000] The compound of any one of paragraphs [00996]-[00999], wherein each Ralpha2 is H [001001] The compound of any one of paragraphs [00996]-[001000], wherein each R1 and each R3 is H.
[001002] The compound of any one of paragraphs [00989]-[001001], wherein the repeating unit occurs at least five times consecutively in the compound.
[001003] The compound of any one of paragraphs [00989]-[001001], wherein the repeating unit occurs at least seven times consecutively in the compound.
[001004] The compound of any one of paragraphs [00989]-[001003], wherein at least a third of the R2 groups in the structure are methyl substituted with a heterocycle.
[001005] The compound of any one of paragraphs [00989]-[001003], wherein at least half of the R2 groups in the structure are methyl substituted with a heterocycle.
[001006] The compound of any one of paragraphs [00989]-[001005], wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
[001007] The compound of any one of paragraphs [00989]-[001006], wherein at least one of the heterocycles of the R2 groups is a divalent nucleobase.
[001008] The compound of any one of paragraphs [00989]-[001007], wherein the heterocycles of the R2 groups are divalent nucleobases.
[001009] The compound of any one of paragraphs [00989]-[001005], wherein the heterocycles of the R2 groups are each independently:
Figure imgf000290_0001
[001010] The compound of any one of paragraphs [00989]-[001005], wherein each R2 is independently: methyl,
Figure imgf000291_0001
[001011] The compound of any one of paragraphs [00989]-[001010], wherein at least a third of the R4 groups in the structure are methyl substituted with a heterocycle.
[001012] The compound of any one of paragraphs [00989]-[001010], wherein at least half of the R4 groups in the structure are methyl substituted with a heterocycle.
[001013] The compound of any one of paragraphs [00989]-[001010], wherein the heterocycles of the R4 groups are nucleobases or analogues of nucleobases.
[001014] The compound of any one of paragraphs [00989]-[001010], wherein at least one of the heterocycles of the R4 groups is a divalent nucleobase.
[001015] The compound of any one of paragraphs [00989]-[001010], wherein the heterocycles of the R4 groups are divalent nucleobases.
[001016] The compound of any one of paragraphs [00989]-[001010], wherein the heterocycles of the R4 groups are each independently:
Figure imgf000291_0002
[001017] The compound of any one of paragraphs [00989]-[001010], wherein each R4 is independently: methyl,
, or
[001018] The compound of any one of paragraphs [00575]-[001017], wherein the compound binds to a sequence of nucleic acids associated with cancer.
[001019] The compound of any one of paragraphs [00575]-[001017], wherein the structure binds to a sequence of nucleic acids encoding a KRAS gene.
[001020] The compound of any one of paragraphs [00575]-[001017], wherein the structure binds to a sequence of nucleic acids encoding a KRAS gene by interactions between the heterocycles of the R2 groups and nucleobases of the KRAS gene.
[001021] The compound of paragraph [001019] or paragraph [001020], wherein the KRAS gene is a non-wild type KRAS gene.
[001022] The compound of paragraph [001021], wherein the non-wild type KRAS gene differs from a wild type KRAS gene in a single nucleotide polymorphism.
[001023] The compound of paragraph [001022], single nucleotide polymorphism causes a mutation that is G12D.
[001024] The compound of paragraph [001022], single nucleotide polymorphism causes a mutation that is G12V.
[001025] The compound of paragraph [001022], single nucleotide polymorphism causes a mutation that is G12C.
[001026] The compound of any one of paragraphs [001019]-[001025], wherein the sequence of nucleic acids is a DNA sequence.
[001027] The compound of any one of paragraphs [001019]-[001025], wherein the sequence of nucleic acids is an mRNA sequence.
[001028] The compound of any one of paragraphs [00575]-[001017], wherein the compound interferes with expression of a cancer-causing protein.
[001029] The compound of paragraph [001028], wherein the cancer causing protein is mutant K-ras. [001030] The compound of paragraph [001028], wherein the cancer causing protein is G12D K- ras.
[001031] The compound of paragraph [001028], wherein the cancer causing protein is G12C K- ras.
[001032] The compound of paragraph [001028], wherein the cancer causing protein is G12V K- ras.
[001033] A compound comprising:
1) a pharmacophore, wherein the pharmacophore is a region that comprises a structure that interferes with expression of a cancer-causing protein; and
2) connected to the pharmacophore, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000293_0001
ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
[001034] The compound of paragraph [001033], wherein each of R1, R3, and R4 is hydrogen; and R2 is NH or N(PgN).
[001035] The compound of paragraph [001033] or paragraph [001034], wherein R5 is linear alkyl.
[001036] The compound of paragraph [001033] or paragraph [001034], wherein R5 is methyl. [001037] The compound of any one of paragraphs [001033]-[001036], wherein n is 3. [001038] The compound of any one of paragraphs [001033]-[001036], wherein n is 4.
[001039] The compound of paragraph [001033], further comprising a first chemical moiety attached to the oligomeric structure, wherein the oligomeric structure, the first chemical moiety, and the pharmacophore form:
Figure imgf000294_0001
, wherein:
E1 is the first chemical moiety, and E2 is the pharmacophore; or E1 is the pharmacophore, and E2 is the first chemical moiety; and p is an integer that is 1-100.
[001040] The compound of paragraph [001039], wherein p is 6.
[001041] The compound of paragraph [001039], wherein p is 7.
[001042] The compound of paragraph [001039], wherein p is 8.
[001043] The compound of any one of paragraphs [001039]-[001042], wherein E1 is the first chemical moiety, wherein the first chemical moiety is hydrogen, acyl, a group that together with the nitrogen atom to which E1 is bound forms a carbamate, a probe, a metal chelator, or an imaging agent; and E2 is the pharmacophore.
[001044] The compound of any one of paragraphs [001039]-[001042], wherein E1 is the pharmacophore; and E2 is the first chemical moiety, wherein the first chemical moiety is OH, OMe, NH2 a probe, a metal chelator, or an imaging agent.
[001045] The compound of any one of paragraphs [001039]-[001042], wherein E1 is hydrogen and E2 is the pharmacophore.
[001046] The compound of any one of paragraphs [001033]-[001045], wherein the cancer- causing protein is mutant K-ras.
[001047] The compound of any one of paragraphs [001033]-[001046], wherein the cancer- causing protein is G12D K-ras.
[001048] The compound of any one of paragraphs [001033]-[001046], wherein the cancer- causing protein is G12C K-ras.
[001049] The compound of any one of paragraphs [001033]-[001046], wherein the cancer- causing protein is G12V K-ras.
[001050] The compound of any one of paragraphs [001033]-[001045], wherein pharmacophore binds to a nucleic acid sequence encoding a cancer gene. [001051] The compound of any one of paragraphs [001033]-[001045], wherein pharmacophore binds to a mRNA sequence transcripted from a cancer gene.
[001052] The compound of any one of paragraphs [001033]-[001045], wherein pharmacophore binds to a DNA sequence encoding a cancer gene.
[001053] The compound of any one of paragraphs [001050]-[001052], wherein the cancer gene is non-wild type KRAS.
[001054] The compound of any one of paragraphs [001050]-[001053], wherein the cancer gene is G12D KRAS
[001055] The compound of any one of paragraphs [001050]-[001053], wherein the cancer gene is G12C KRAS.
[001056] The compound of any one of paragraphs [001050]-[001053], wherein the cancer gene is G12V KRAS
[001057] The compound of any one of paragraphs [001033]-[001056], wherein the pharmacophore is an oligonucleotide or oligonucleotide analogue.
[001058] The compound of any one of paragraphs [001033]-[001056], wherein the pharmacophore is a peptide nucleic acid.
[001059] The compound of paragraph [001033], wherein the compound is:
Figure imgf000295_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L3 is a linker group or absent;
N-Terminus is H, acyl, a group that together with the nitrogen atom to which the A-Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
[001060] The compound of paragraph [001059], wherein L3 is absent.
[001061] The compound of paragraph [001059] or paragraph [001060], wherein N-terminus is H.
[001062] The compound of any one of paragraphs [001059]-[001061 ], wherein C-Terminus is
NH2.
[001063] The compound of any one of paragraphs [001059]-[001062], wherein each instance of
Q1 Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen. [001064] The compound of paragraph [001033], wherein the compound is:
Figure imgf000296_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L4 is a linker group or absent; N-Terminus is H, acyl, a group that together with the nitrogen atom to which the N-Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
[001065] The compound of paragraph [001064], wherein L4 is absent.
[001066] The compound of paragraph [001064] or paragraph [001065], wherein /V-Terminus is H.
[001067] The compound of any one of paragraphs [001064]-[001066], wherein C-Terminus is NH2
[001068] The compound of any one of paragraphs [001064]-[001067], wherein each instance of
Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen. [001069] A compound comprising a structure that is:
N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1-ξ-
Figure imgf000297_0001
wherein: the number of units with variables defined independently is at least 11; N-Terminus is H, acyl, a group that together with the nitrogen atom to which the N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralph a is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, O-alkyl, a peptide sequence, or NH2;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent;
L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof, wherein the compound interferes with expression of a cancer-causing protein.
[001070] The compound of paragraph [001069], wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27. [001071] The compound of paragraph [001069] or paragraph [001070], wherein N-Terminus is H and C-Terminus is NH2
[001072] The compound of any one of paragraphs [001069]-[001071 ], wherein each R1 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
[001073] The compound of any one of paragraphs [001069]-[001071 ], wherein at least one iteration of R1 is hydroxylmethyl.
[001074] The compound of any one of paragraphs [001069]-[001071], wherein at least half the iterations of R1 are hydroxylmethyl and the other iterations of R1 are H.
[001075] The compound of any one of paragraphs [001069]-[001074], wherein each of L1, L2, L3, L4, L5, and L6 is absent.
[001076] The compound of any one of paragraphs [001069]-[001075], wherein SOL1 and SOL2 are absent.
[001077] The compound of any one of paragraphs [001069]-[001076], wherein one of PEP1 and PEP2 is a peptide sequence that is a nuclear localization sequence and the other is absent. [001078] The compound of any one of paragraphs [001069]-[001077], wherein one of PEP1 and PEP2 is -Pro-Lys-Lys-Lys-Arg-Lys-Val- (SEQ ID NO: 1).
[001079] The compound of any one of paragraphs [001069]-[001077], wherein one of PEP1 and PEP2 is -Pro-Ala-Ala-Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2).
[001080] The compound of any one of paragraphs [001069]-[001075], wherein PEP1 and PEP2 are absent.
[001081] The compound of any one of paragraphs [001069]-[001075], wherein SOL1 is the water-solubilizing group and SOL2 is absent.
[001082] The compound of any one of paragraphs [001069]-[001075], wherein each of L1, L2, L3, L4, L5, L6, PEP1, PEP2, and SOL2 is absent, and SOL1 is the water-solubilizing group. [001083] The compound of any one of paragraphs [001069]-[001075], [001081], and [001082], wherein the water-solubilizing group is a group that contains multiple positive charges at physiological pH.
[001084] The compound of any one of paragraphs [001069]-[001075] and [001081]-[001083], wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000299_0001
, wherein
R1a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is alkyl or O-alkyl, any of which is unsubstituted or substituted; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-100.
[001085] The compound of paragraph [001084], wherein p is 5, 6, 7, or 8.
[001086] The compound of paragraph [001084], wherein p is 7.
[001087] The compound of any one of paragraphs [001069]-[001075] and [001081 ]-[001086], wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000299_0002
wherein p is an integer that is 5, 6, 7, or 8.
[001088] The compound of any one of paragraphs [001069]-[001075] and [001081 ]-[001086], wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000299_0003
wherein p is an integer that is 5, 6, 7, or 8.
[001089] The compound of paragraph [001087] or paragraph [001088], wherein p is 7.
[001090] The compound of any one of paragraphs [001069]-[001089], wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
[001091] The compound of any one of paragraphs [001069]-[001090], wherein the heterocycles of the R2 groups are each independently: , or
[001092] The compound of any one of paragraphs [001069]-[001090], wherein each R2 group in the structure is independently:
[001093] The compound of any one of paragraphs [001069]-[001092], wherein the number of units with variables defined independently is 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl; and R2 is a second unit is present or absent, and in the second unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000301_0001
a third unit is present, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000301_0002
a fourth unit is present, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000301_0003
a fifth unit is present, and in the fifth unit:
R is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000301_0004
a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000301_0005
a seventh unit is present, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000301_0006
a n eighth unit is present, and in the eighth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is or a ninth unit is present, and in the ninth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is
; or a tenth unit is present, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is an eleventh unit is present, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000303_0001
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000303_0002
a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000303_0003
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000303_0004
a sixteenth unit is present, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000303_0005
and a seventeenth unit is present or absent, and in the seventeenth unit:
Figure imgf000304_0001
[001094] The compound of any one of paragraphs [001069]-[001092], wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000304_0002
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000304_0003
O a third unit is present or absent, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000304_0004
a fourth unit is present or absent, and in the fourth unit: R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000305_0001
a fifth unit is present, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000305_0002
O a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1 yl;
Figure imgf000305_0003
a seventh unit is present, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000305_0004
an eighth unit is present, and in the eighth unit: 1
Figure imgf000305_0005
a ninth unit is present, and in the ninth unit: 1
Figure imgf000306_0005
a tenth unit is present, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000306_0001
an eleventh unit is present, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut- 1yl;
Figure imgf000306_0002
O a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000306_0003
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000306_0004
a fourteenth unit is present, and in the fourteenth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000307_0001
O a fifteenth unit is present or absent, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000307_0002
a sixteenth unit is present or absent, and in the sixteenth unit:
R is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000307_0003
and a seventeenth unit is present or absent, and in the seventeenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000307_0005
[001095] The compound of any one of paragraphs [001069]-[001092], wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000307_0004
a second unit is present or absent, and in the second unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000308_0001
a third unit is present or absent, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000308_0002
a fourth unit is present or absent, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is
Figure imgf000308_0003
a fifth unit is present or absent, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000308_0004
a sixth unit is present or absent, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000308_0005
a seventh unit is present or absent, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000308_0006
an eighth unit is present or absent, and in the eighth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000309_0001
a ninth unit is present or absent, and in the ninth unit:
R is H, -CH2OH, or 4-guanidinobut-1-yl; and R is
Figure imgf000309_0002
a tenth unit is present or absent, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000309_0003
an eleventh unit is present or absent, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000309_0004
a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000309_0005
a thirteenth unit is present, and in the thirteenth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000310_0001
a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000310_0002
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000310_0003
O a sixteenth unit is present, and in the sixteenth unit: 1
Figure imgf000310_0005
a seventeenth unit is present, and in the seventeenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000310_0004
O an eighteenth unit is present, and in the eighteenth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000311_0001
a nineteenth unit is present, and in the nineteenth unit:
R is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000311_0002
R2 is a twentieth unit is present, and in the twentieth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000311_0003
a twenty-first unit is present, and in the twenty -first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000311_0004
a twenty-second unit is present or absent, and in the twenty-second unit:
R is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000311_0005
R2 is a twenty-third unit is present or absent, and in the twenty-third unit:
R is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000311_0006
R2 is a twenty-fourth unit is present or absent, and in the twenty-fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000312_0001
a twenty-fifth unit is present or absent, and in the twenty -fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000312_0002
a twenty-sixth unit is present or absent, and in the twenty-sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000312_0003
a twenty-seventh unit is present or absent, and in the twenty-seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000312_0004
[001096] The compound of any one of paragraphs [001069]-[001095], wherein the compound binds to a nucleic acid sequence encoding the cancer-causing protein.
[001097] The compound of any one of paragraphs [001069]-[001096], wherein the cancer- causing protein is mutant K-ras.
[001098] The compound of any one of paragraphs [001069]-[001096], wherein the cancer- causing protein is G12D K-ras.
[001099] The compound of any one of paragraphs [001069]-[001096], wherein the cancer- causing protein is G12C K-ras.
[001100] The compound of any one of paragraphs [001069]-[001096], wherein the cancer- causing protein is G12V K-ras.
[001101] The compound of paragraph [001097], wherein the compound binds to the nucleic acid sequence encoding the mutant K-ras by interactions between the heterocycles of the R2 groups and nucleobases of the nucleic acid sequence.
[001102] The compound of paragraph [001101], wherein the nucleic acid sequence is a mRNA sequence.
[001103] The compound of paragraph [001101], wherein the nucleic acid sequence is a DNA sequence.
[001104] A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of any one of paragraphs [001069]-[001095] .
[001105] The method of paragraph [001104], wherein the condition is cancer.
[001106] The method of paragraph [001104] or paragraph [001105], wherein the condition is associated with a non- wild type gene in the subject, wherein the non-wild type gene differs from a corresponding wild type gene in a single nucleotide polymorphism.
[001107] The method of paragraph [001106], wherein the non-wild type gene is non-wild type KRAS
[001108] The method of paragraph [001107], wherein the non-wild type KRAS gene is G12D KRAS
[001109] The method of paragraph [001107], wherein the non-wild type KRAS gene is G12C KRAS
[001110] The method of paragraph [001107], wherein the non-wild type KRAS gene is G12V KRAS
[001111] The method of any one of paragraphs [001104]-[001107], wherein the condition is pancreatic ductal adenocarcinoma, lung adenocarcinoma, multiple myeloma, pancreatic ductal adenocarcinoma, or multiple myeloma.
[001112] The method of any one of paragraphs [001104]-[001111], wherein the subject is human.
EXAMPLES
EXAMPLE 1: Synthesis and purification of Compounds of the disclosure.
[001113] Synthesis of crude PNA: PNA synthesis was performed using Fmoc solid-phase peptide chemistry on an Intavis MultiPep RSi (25 μmol scale) at ambient temperature. TentaGel® R RAM resin (0.18 meq/g) was swelled in N,N-dimethylformamide (DMF) (1 mL, 3 x 10 min). Fmoc groups were deprotected with 20% piperidine (v/v) in DMF (0.8 mL, 2 x 10 minutes). Following deprotection, the resin was washed with DMF (6 x 1 mL) and the next PNA residue was coupled to the N-terminus of resin-bound PNA upon treatment with a mixture of Fmoc-protected monomer (85 μmol , 3.4x, 0.2 M in NMP), HATU (80 μmol, 3.2x, 0.5 M in DMF), and N,N-diisopropylethylamine (DIPEA, 83 μmol, 3.3x, 0.52 M in DMF) (double coupling: 2 min pre-activation and 30 min coupling). After coupling, the resin was acetyl capped with 5% acetic anhydride and 6% 2,6-lutidine (v/v) in DMF (5 min), and subsequently washed with DMF (6 x 1 mL). Upon completion of all synthetic cycles, the resin was washed with DMF (5x) and DCM (5x). PNA was simultaneously cleaved and deprotected upon treatment with a mixture of trifluoroacetic acid/triflic acid/thioanisol/m-cresol (5 mL, 6:2: 1:1) under agitation for 90 minutes. PNA was precipitated in ice-cold diethyl ether (45 mL), spun by centrifuge, isolated from the supernatant, washed with ice-cold diethyl ether (50 mL), and dried under vacuum. [001114] Purification of PNA: Crude PNA was dissolved in Milli-Q water (5 mL) and filtered through a nylon syringe-tip filter (0.45 pm pore size). Preparative reversed-phase high-pressure liquid chromatography (RP-HPLC) was performed on a Dionex Ultimate™ 3000 equipped with a Hypersil GOLD™ C18aq 30 x 250 mm column, with a 5 pm particle size and 175 A pore size. A 30-minute linear gradient of acetonitrile (5-25%) in water with 0.1% TFA was used as the mobile phase. HPLC eluate was fractionated based on UV absorbance (λ = 254 nm) and fractional purity was assessed via MALDI-TOF in linear positive mode with a matrix of CHCA. Pure fractions were lyophilized, dissolved in water, combined, and re-lyophilized. Pure PNA was dissolved in PBS and the concentration of the PNA solution was determined via absorbance spectroscopy (e (λ = 260 nm) = 148,300 cm-1 M-1). Selected compounds were characterized by matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS) or ESI+MS. Observed masses are presented in TABLE 8.
TABLE 8
Cpd Observed Mass SEQ
Structure Code (N to C terminus)*
# [M+l] ID NO°
YgYgYgYgYgYgYgTsGnGsAnGsCnTsGnAsTnGsGnCsGnTsAnGs 1
43 {PKKKRKV} 7658, 7661
6793, 6795,
44 YgYgYgYgYgYgYgTsGnGsAnGsCnTsGnAsTnGsGnCsGnTsAnGs 6797
48 YgYgYgYgYgYgYgTsYnGsAnYsCnTsGnAsTnYsGnCsYnTsAnGs 6201 -
YgYgYgYgYgYgYgTsYnGsDnYsCnTsGnDsTnYsGnCsYnTsDnGs
49 {PKKKRKV} 7114, 7119 1
6240, 6242,
50 YgYgYgYgYgYgYgTsYnGsDnYsCnTsGnDsTnYsGnCsYnTsDnGs 6245
YgYgYgYgYgYgYgGsDnGsCnTsGnDsTnGsGnCsGnTsDn{PKKKR
51 KV} 6796 1
YgYgYgYgYgYgYgGsAnGsCnSsGnAsSnGsGnCsGnSsAn{PKKKR 1
52 KV} 6754, 6757
YgYgYgYgYgYgYgGsAnGsCnTsGnAsTnGsGnCsGnTsAn{PKKKR 1
53 KV} 6751
YgYgYgYgYgYgYgGsAnGsCnTsGnAsTnGsGnCsGnTsAn{PKKKR 1
62 KV} 6755, 6759
5891, 5889, —
63 YgYgYgYgYgYgYgGsAnGsCnTsGnAsTnGsGnCsGnTsAn 5894 Cpd Observed Mass SEQ
Structure Code (N to C terminus)*
# [M+1] ID NOc
67 YgYgYgYgYgYgYgGsAnYsCnTsGnAsTnYsGnCsYnTsAn 5439, 5441 -
69 YgYgYgYgYgYgYgGsDnYsCnTsGnDsTnYsGnCsYnTsDn 5486, 5491 -
71 YgYgYgYgYgYgYgTsGnGsAnGsCnTsGnTsTnGsGnCsGnTsAnGs 6781, 6784 -
73 YgYgYgYgYgYgYgTsYnGsAnYsCnTsGnTsTnYsGnCsYnTsAnGs 6189 -
-
75 YgYgYgYgYgYgYgTsYnGsDnYsCnTsGnTsTnYsGnCsYnTsDnGs 6218, 6221
YgYgYgYgYgYgYgGsDnGsCnTsGnTsTnGsGnCsGnTsDn{PKKKR 1
76 KV} 6769, 6772
YgYgYgYgYgYgYgGsAnGsCnSsGnSsSnGsGnCsGnSsAn{PKKKR 6750, 6753, 1
78 KV} 6755, 6757
YgYgYgYgYgYgYgGsAnYsCnSsGnSsSnYsGnCsYnTsAn{PKKKR 6298, 6301, 1
79 KV} 6303
YgYgYgYgYgYgYgGsAnGsCnTsGnTsTnGsGnCsGnTsAn{PKKKR 1
80 KV} 6741, 6744
-
90 YgYgYgYgYgYgYgGsAnGsCnTsGnTsTnGsGnCsGnTsAn 5877, 5881
-
91 YgYgYgYgYgYgYgZsAnZsCnTsZnTsTnZsZnCsZnTsAn 5874.6
YgYgYgYgYgYgYgGsAnYsCnTsGnTsTnYsGnCsYnTsAn{PKKKR 1
92 KV} 6297
95 YgYgYgYgYgYgYgGsDnYsCnTsGnTsTnYsGnCsYnTsDn 5464 -
YgYgYgYgYgYgYgGsGnDsGnCsTnTsGnTsGnGsCnGsTn{PKKKR 1
96 KV} 6771, 6774
YgYgYgYgYgYgYgGsGnAsGnCsSnSsGnSsGnGsCnGsSn{PKKKR 1
97 KV} 6762, 6766
YgYgYgYgYgYgYgGsGnAsGnCsTnTsGnTsGnGsCnGsTn{PKKKR 1
98 KV} 6761
YgYgYgYgYgYgYgTsGnGsAnGsCnTsTnGsTnGsGnCsGnTsAnGs 1
99 {PKKKRKV} 7650, 7654
6785, 6790, —
100 YgYgYgYgYgYgYgTsGnGsAnGsCnTsTnGsTnGsGnCsGnTsAnGs 6788
YgYgYgYgYgYgYgTsYnGsAnYsCnTsTnGsTnYsGnCsYnTsAnGs 1
101 {PKKKRKV} 7055
-
102 YgYgYgYgYgYgYgTsYnGsAnYsCnTsTnGsTnYsGnCsYnTsAnGs 6794, 6798
YgYgYgYgYgYgYgTsYnGsDnYsCnTsTnGsTnYsGnCsYnTsDnGs 1
103 {PKKKRKV} 7088, 7092
104 YgYgYgYgYgYgYgTsYnGsDnYsCnTsTnGsTnYsGnCsYnTsDnGs 6220, 6225 -
106 YgYgYgYgYgYgYgGsAnGsCnTsTnGsTnGsGnCsGnTsAn 5882, 5879 -
YgYgYgYgYgYgYgGsAnYsCnTsTnGsTnYsGnCsYnTsAn{PKKKR 1
107 KV} 6296
-
108 YgYgYgYgYgYgYgGsAnYsCnTsTnGsTnYsGnCsYnTsAn 5433, 5437
110 YgYgYgYgYgYgYgGsDnYsCnTsTnGsTnYsGnCsYnTsDn 5466 -
144 YgYgYgYgYgYgYgGsCnTsGnAsTnGsGn 4147 -
145 YgYgYgYgYgYgYgGsCnTsGnAsTnGsGnCs 4427.9 -
146 YgYgYgYgYgYgYgGsCnTsGnAsTnGsGnCsGn 4719.8 -
-
147 YgYgYgYgYgYgYgGsCnTsGnAsTnGsGnCsGnTs 5017.3
148 YgYgYgYgYgYgYgGsAnGsCnTsGnAsTnGsGnCsGn 5313.6 -
149 YgYgYgYgYgYgYgGsAnGsCnTsGnAsTnGsGnCsGnTs 5611 -
150 YgYgYgYgYgYgYgTsGnGsAnGsCnTsGnAsTnGsGnCsGnTs 6194.1 -
151 YgYgYgYgYgYgYgGsAnGsCnTsGnTsTnGsGnCsGn 5305.4 - Cpd Observed Mass SEQ
Structure Code (N to C terminus) *
# [M+1 ] ID NOc
152 YgYgYgYgYgYgYgGsAnGsCnTsGnTsTnGsGnCsGnTs 5006 . 6
153 YgYgYgYgYgYgYgTsGnGsAnGsCnTsGnTsTnGsGnCsGnTs 6191 . 1
6462 . 3 ,
154 YgYgYgYgYgYgYgTsGnGsAnGsCnTsGnTsTnGsGnCsGnTsAn 6467 . 5
155 YgYgYgYgYgYgYgGsCnTsGnTsTnGsGn 4138 . 2
156 YgYgYgYgYgYgYgGsCnTsGnTsTnGsGnCs 4420 . 2
157 YgYgYgYgYgYgYgGsCnTsGnTsTnGsGnCsGn 4712 . 8
158 YgYgYgYgYgYgYgGsCnTsGnTsTnGsGnCsGnTs 5010 . 5
203 YgYgYgYgYgYgYgTsZnZ sAnZ sCnTsTnGsTnZ sZnCsZnTsAnGs 6783 . 2
-
204 YgYgYgYgYgYgYgGsCnCsAnTsCnAsGnCsTn 4623 . 4
-
205 YgYgYgYgYgYgYgCnGs CnCsAnTs CnAs GnCsTnCs 5154 . 5
-
206 YgYgYgYgYgYgYgAsCnGsCnCsAnTsCnAsGnCsTnCsCn 5723 . 7 (M+l 2 )
207 YgYgYgYgYgYgYgTnAs CnGs CnCsAnTs CnAs GnCsTnCs CnAs 6283 . 2
YgYgYgYgYgYgYgGsCnCsTnAsCnGs CnCsAnTs CnAs GnCsTnCs
208 CnAsAn 7411 . 7
209 YgYgYgYgYgYgYgCnGs CnCsYnTsYnAs GnCsTnCs 4913 . 3
210 YgYgYgYgYgYgYgTnAs CnGs CnCsYnTsYnAs GnCsTnCs CnAs 6044 . 6 (M+5 )
YgYgYgYgYgYgYgGsCnCsTnAsCnGs CnCsYnTsYnAs GnCsTnCs
211 CnAsAn 7168 . 4
212 YgYgYgYgYgYgYgCnGs CnCnAnTsCnAnGnCsTnCn 5066 . 6 (M+2 )
213 YgYgYgYgYgYgYgTnAnCnGsCnCnAnTsCsAnGnCsTnCnCnAs 6162 . 0
YgYgYgYgYgYgYgGnCnCsTnAnCnGs CnCnAnTsCnAnGnCsTnCn
214 CnAsAn 7261 . 8
215 YgYgYgYgYgYgYgCnGs CnCnYnTs YnAnGnCsTnCn 4824 . 1
216 YgYgYgYgYgYgYgTnAnCnGsCnCnYnTs YnAnGnCsTnCnCnAs 5921 . 3
YgYgYgYgYgYgYgGnCnCsTnAnCnGsCnCnYnTs YnAnGnCsTnCn
217 CnAsAn 7018 . 5
218 YgYgYgYgYgYgYgTsAnCsGsCsCnAsTsCsAnGsCsTsCnCsAs 6403 . 4
219 YgYgYgYgYgYgYgTsAnCsGsCsCnYsTs YsAnGsCsTsCnCsAs 6166 . 0 (M+6 )
YgYgYgYgYgYgYgGsCsCsTsAsCsGsCsCsAsTsCsAsGsCsTsCs —
220 CsAsAs 7710.5
^Portion of structure code within braces (e.g., {PKKKRKV}”), when present, correspond to
SEQ ID NO provided in this column.
EXAMPLE 2: In vivo tumor growth inhibition via RNA targeting of G12D mutation using Compound 1.
[001115] In vivo tumor growth inhibition via RNA targeting of the G12D mutation was assessed using Compound 1 as shown in FIG. 1. The study was performed in SCID mice approximately 5-9 weeks old. Mice were inoculated with HPAF-II cells (1 million cells/mouse) by subcutaneous injection. The study was initiated once the tumor volumes reached a target size of 100 mm3. Mice were dosed intratumorally with Compound 1 at 0.3, 1, 3, 10, or 30 μM once per week for three consecutive weeks. Tumor volumes and body weights were collected twice per week. The study was terminated when the tumors reached 1500 mm3 in size.
[001116] Inhibition of tumor growth was observed after 0.3 mg/kg intra-tumoral injections into HPAFII heterozygous pancreatic cancer xenografts. Statistically-significant growth inhibition was achieved 8 days after the first dose.
EXAMPLE 3: In vivo mutant KRAS knock-down decreases downstream signaling using Compound 1.
[001117] Reduction in phosphorylation levels of multiple pathway members in oncogenic cascade was assessed using Compound 1. Frozen tumor samples were laser microdissected and analyzed using a reverse phase protein array for analytes of interest. Reduction in oncogenic signaling through the entire RAS pathway was measured using phospho-specific antibodies. FIG. 2, Panel A illustrates an overview of the cell-signaling pathway downstream of RAS. As illustrated in FIG. 2, Panels B-E, significant reduction in aberrant signaling was observed across multiple pathway members downstream of RAS, such as MEK (Panel B), ERK (Panel C), CREB (Panel D), and RSK3 (Panel E).
EXAMPLE 4: In vivo tumor growth inhibition via RNA targeting of G12V mutation using Compound 2.
[001118] In vivo tumor growth inhibition via RNA targeting of G12V mutation was assessed using Compound 2 as shown in FIG. 3. The study was performed in SCID mice approximately 5-9 weeks old. Mice were inoculated with CAP AN-2 F-II cells (5 million cells/mouse) by subcutaneous injection. The study was initiated once the tumor volumes reached a target size of 100 mm3. Mice were dosed intratumorally with Compound 2 at 0.3, 1, 3, 10, or 30 mM once per week for three consecutive weeks. Tumor volumes and body weights were collected twice per week.
[001119] Inhibition of tumor growth was observed after 0.3 mg/kg intra-tumoral injections into CAP AN-2 heterozygous pancreatic cancer xenografts. Prolonged tumor growth inhibition was achieved after 3 doses.
EXAMPLE 5: Evaluation of compounds in HPAF II human pancreas tumor xenograft model.
[001120] The anti-tumor activity of Compounds 5 and 6 as single agents were evaluated in the HPAF II human pancreas tumor xenograft model, which displays the G12D KRAS mutation target. The significant endpoint was tumor growth inhibition.
[001121] Test system: ICR SCID (IcrTac:ICR-Prkdcscid), physiologically normal mice were inoculated at 7 weeks of age. 54 Female mice were used, and the animals were not replaced during the duration of the study.
[001122] Animal housing and environment: The mice were kept in individually ventilated microisolator cages and were acclimated for at least 5-7 days. The mice were maintained under pathogen-free conditions. Food and water were provided ad libitum. The mice were provided with Teklad Global Diet® 2920x irradiated pellets and autoclaved water. DietGel® 76Awas provided as needed for supplemental nutrition.
[001123] Vehicle mixture-control: The vehicle control used in the study was PBS (pH 7.4) + Invivofectamine® 3.0. 59 μL of complexation buffer was added to 59 pL of PBS (pH 7.4). 119 pL of Invivofectamine 3.0 was then added, mixed by vortex, incubated at 50 °C for 30 minutes, and spun by centrifuge briefly to collect the sample. 230 pL of the PBS / Invivofectamine complex was further diluted with 170 pL PBS to obtain a ratio and dilution of Invivofectamine 3.0 / complexation buffer that matched the most concentrated dosing solution (0.3450 mg/mL). The vehicle was a white solution and made fresh for each dosing every day.
[001124] Administration of vehicle control: The vehicle control was administered by intratumorally (IT), once weekly for 3 weeks (QWx3). 50 pL fixed volume was administered. [001125] Test articles: Compound 5 and Compound 6 were clear liquids, and stored at -80 °C. The 30 pM and 10 pM groups were white solutions, and the 3 μM and 0.3 μM groups were clear solutions. Compound 5 (5.63 mg/mL) and Compound 6 (5.93 mg/mL) were heated at 80 °C for 10 minutes after thawed to ensure that the PNA was fully denatured. The compounds were agitated lightly by vortex. An aliquot was removed from each respective test article and each were diluted in PBS (pH 7.4) to obtain 100 μL of a 2.4 mg/mL PNA solution. 100 μL of complexation buffer was added to 100 μL of the PNA solution to provide a 1.2 mg/mL solution for transfection. 200 μL of Invivofectamine 3.0 was added to obtain a concentration of 0.6 mg/mL, then mixed by vortex, incubated at 50 °C for 30 minutes, and spun by centrifuge briefly to collect the sample. The Compound 5 / Invivofectamine complex was further diluted with PBS to obtain a solution of 0.3274 mg/mL (Group 5) to deliver a dose of 30 μM/dose in a 50 μL/dose volume. Portions of the Group 5 solution were further diluted in PBS to concentrations of 0.0033 mg/mL (Group 2), 0.0327 mg/mL (Group 3), and 0.1091 mg/mL (Group 4) to deliver doses of 0.3 μM/dose, 3 μM/dose, and 10 μM/dose, respectively, in a 50 μL/dose volume. The Compound 6 / Invivofectamine complex was further diluted with PBS to obtain a solution of 0.3450 mg/mL (Group 9) to deliver a dose of 30 pM/dose in a 50 μL/dose volume. Portions of the Group 9 solution were further diluted in PBS to concentrations of 0.0034 mg/mL (Group 6), 0.0345 mg/mL (Group 7), and 0.1150 mg/mL (Group 8) to deliver doses of 0.3 μM/dose, 3 μM/dose, and 10 μM/dose, respectively, in a 50 μL/dose volume. The PNA stock solutions were refrozen within one hour of thawing. Dosing solutions were made fresh on each dosing day. [001126] Treatment groups: Compound 5 and Compound 6 were administered intratumorally (IT), once weekly for 3 weeks (QWx3). Dose concentration calculations were based on actual tumor volume mean at the time of randomization. 50 μL fixed volume was administered. The treatment groups are shown in TABLE 9.
TABLE 9
Treatment group N Dose (QWx3)
6 Vehicle
1
6 Compound 5; 0.3 μM
2
6 Compound 5; 3 μM
3
6 Compound 5; 10 μM
4
6 Compound 5; 30 μM
5
6 Compound 6; 0.3 μM
6
6 Compound 6; 3 μM
7
6 Compound 6; 10 μM
8
6 Compound 6; 30 μM
9
[001127] Experimental design: The cell line used was HPAF II, and the number of cells injected was 1 x 106 cells/mouse. The cell growth media was RPMI medium with 10% fetal bovine serum (FBS) + 1% penicillin/streptomycin. The cells were grown under 5% CO2 with a split ratio of 1 : 10. The cells were inoculated subcutaneously in the right flank using an inoculation vehicle of 50% Matrigel and 50% media in 0.1 mL. Subcutaneous tumor sizes were calculated using the following equation: Tumor volume (mm3) = (a x b2/2), where “b” is the smallest diameter and “a” is the largest diameter. The study was initiated when the mean tumor volume was 97 mm3. Samples were randomized using random equilibration of tumor volume. Treatment initiation started on day 1 of the dosing schedule shown in TABLE 9 above. Tumor volume and body weight were measured twice weekly, and gross observations were made daily. Each group was euthanized when individual group mean tumor volume reached > 1,500 mm3 or on day 29 when the final groups reached the study endpoint.
[001128] Tissue collection: No in-study collections occurred. At individual group endpoint, tumors from three mice per group (one each of high, medium, and low tumor volumes) were excised. Tumors were bisected and a wet weight was taken of each piece. One tumor piece was placed in a cryovial, snap frozen in liquid nitrogen, and stored at -80 °C. The remaining tumor piece was fixed in 10% neutral buffered formalin for 48-72 hours before being transferred to 70% ethanol, then paraffin blocked. Paraffin blocks were stored at room temperature Frozen tumor samples from Groups 2, 3, 4, 6, 7, and 8 and all paraffin blocks were retained for possible future analysis.
[001129] Data and statistical analysis: Mean tumor growth inhibition (TGI) was calculated for Day 22 (the final day all groups were on study) utilizing the following formula. Individual student's t-test was calculated for Day 22 using animal study management software, Study Director. P< 0.05 was considered statistically significant.
(X Treated (final) X Treated (Day 1))
TGI = 1 — X 100%
(X Vehicle Control ( final ) - X Vehicle Control (Day X1)
[001130] TABLE 10 shows day 22 mean tumor volumes, tumor growth inhibition, and
Student's t-test.
TABLE 10
Treatment Dose (QWx3) Day 22 group Day 22 Mean Day 22 Student’s t- Tumor Volume test (mm3) ± SEM % TGI
(p value)*
Vehicle 1,720.9 ±
1 — - 256.5
Compound 5; 0.3 μM 1,458.9 ±
2 16.2 0.392 207.1
Compound 5; 3 μM 1,484.0 ±
3 14.6 0.398 172.1
Compound 5; 10 μM 1,473.4 ± 92.2 15.2 0.322
4
Compound 5; 30 μM 1,333.0 ±
5 23.9 0.246 210.8
Compound 6; 0.3 μM 1,015.2 ±
6 43.5 0.045* 163.1
Compound 6; 3 μM 1,353.2 ±
7 22.7 0.235 173.8
Compound 6; 10 μM 1,260.1 ± 99.8 28.4 0.113
8
Compound 6, 30 μM 1,060.3 ±
9 40.7 0.056 161.8
* p < 0.05 is considered statistically significant
[001131] Differences in time to group endpoint of mean tumor volume greater than or equal to 1,500 mm3 (survival) were calculated with a comparison of each group to the vehicle control group. TABLE 11 shows time to group endpoint and improvement in survival. TABLE 11 3 μM μM μM μM μM μM μM μM
Figure imgf000321_0001
[001132] Conclusions: An efficacy assessment based on tumor growth inhibition showed antitumor activity in all treatment groups. Statistically significant efficacy was observed in the group treated with 0.3 μM of Compound 6, which demonstrated a TGI of 43.5% on Day 22 when compared to the vehicle control group. Treatment with 30 μM of Compound 6 performed similarly with a TGI of 40.7% on Day 22. However, statistical significance was not reached (p = 0.056). A secondary assessment of efficacy was determined by tumor growth delay (survival) in treatment groups compared to the vehicle control. An increase in time to group mean tumor size endpoint was observed in all treatment groups. Treatment with 0.3 μM of Compound 6 and 30 μM of Compound 6 resulted in the largest improvement in survival at 7 days longer than vehicle control. FIG. 4 shows the effect of Compound 5 and Compound 6 on HPAFII tumor volume when administered at doses of 0 μM, 0.3 pM, 3 μM, 10 μM, and 30 μM (IT; QWx3). [001133] Treatment with the compounds was generally tolerated. Mild to marked mean body weight loss was observed in all groups, including vehicle control during dosing cycle. FIG. 5 shows the effect of Compound 5 and Compound 6 on body weight of mice inoculated with HPAFII cells when administered at a dose of 0.3 μM, 3 μM, 10 μM, and 30 μM (IT; QWx3). Generally, weights began to improve following treatment cessation. Tumor necrosis was seen in all groups, which is typical for this tumor model and was non-impactful on study outcome. No other notable clinical observations were recorded throughout the study.
[001134] FIG. 6 shows the effect of treatment on tumor volumes when animals were treated with vehicle, 0.1 mg/kg, and 0.3 mg/kg of Compound 6. On Day 22, the vehicle group reached maximum tumor volume and was sacrificed.
EXAMPLE 6: Evaluation of compounds in Capan-2 human pancreas tumor xenograft model.
[001135] The anti-tumor activities of Compound 7 and Compound 8 as single agents were investigated in the Capan-2 human pancreas tumor xenograft model. This model displays the G12V KRAS mutation target. The significant endpoint was tumor growth inhibition.
[001136] Test system: ICR SCID (IcrTac:ICR-Prkdcscid), physiologically normal mice were inoculated at 6 weeks of age. 54 Female mice were used, and the animals were not replaced during the duration of the study.
[001137] Animal housing and environment: The mice were kept in individually ventilated microisolator cages and were acclimated for at least 5-7 days. The mice were maintained under pathogen-free conditions. Food and water were provided ad libitum. The mice were provided with Teklad Global Diet® 2920x irradiated pellets and autoclaved water.
[001138] Vehicle mixture-control: The vehicle control used in the study was PBS (pH 7.4) + Invivofectamine® 3.0. 56 μL of complexation buffer was added to 56 μL of PBS (pH 7.4). 113 μL of Invivofectamine 3.0 was then added. The resultant mixture was agitated by vortex, incubated at 50 °C for 30 minutes, and spun by centrifuge briefly to collect the sample. 224 μL of the PBS / Invivofectamine complex was further diluted with 176 μL PBS to obtain a ratio and dilution of Invivofectamine 3.0 / complexation buffer that matched the most concentrated dosing solution (0.3355 mg/mL). The vehicle was a white solution and made fresh for each dosing every day.
[001139] Administration of vehicle control: The vehicle control was administered intratumorally (IT), once weekly for 3 weeks (QWx3). 50 μL fixed volume was administered. [001140] Test articles: Compound 7 and Compound 8 were clear liquids, and stored at -80 °C. The 30 μM and 10 μM groups were white solutions, and the 3 μM and 0.3 μM groups were clear solutions. Compound 7 (5.63 mg/mL) and Compound 8 (5.03 mg/mL) were heated at 80 °C for 10 minutes after thawed to ensure that the PNA was fully denatured. The mixture was lightly agitated by vortex. An aliquot was removed from each respective test article and each were diluted in PBS (pH 7.4) to obtain 100 μL of a 2.4 mg/mL PNA solution. 100 μL of complexation buffer was added to 100 μL of the PNA solution to provide a 1.2 mg/mL solution for transfection. 200 μL of Invivofectamine 3.0 was added to obtain a concentration of 0.6 mg/mL. The resultant mixture was agitated by vortex, incubated at 50 °C for 30 minutes, and spun by centrifuge briefly to collect the sample. The Compound 7 / Invivofectamine complex was further diluted with PBS to obtain a solution of 0.3355 mg/mL (Group 5) to deliver a dose of 30 μM/dose in a 50 μL/dose volume. Portions of the Group 5 solution were further diluted in PBS to concentrations of 0.0034 mg/mL (Group 2), 0.0336 mg/mL (Group 3), and 0.1118 mg/mL (Group 4) to deliver doses of 0.3 μM/dose, 3 μM/dose, and 10 μM/dose, respectively, in a 50 μL/dose volume. The Compound 8 / Invivofectamine complex was further diluted with PBS to obtain a solution of 0.2999 mg/mL (Group 9) to deliver a dose of 30 μM/dose in a 50 μL/dose volume. Portions of the Group 9 solution were further diluted in PBS to concentrations of 0.0030 mg/mL (Group 6), 0.0300 mg/mL (Group 7), and 0.1000 mg/mL (Group 8) to deliver doses of 0.3 μM/dose, 3 μM/dose, and 10 μM/dose, respectively, in a 50 μL/dose volume. The PNA stock solutions were refrozen within one hour of thawing. Dosing solutions were made fresh on each dosing day.
[001141] Treatment groups: Compound 7 and Compound 8 were administered intratumorally (IT), once weekly for 3 weeks (QWx3). Dose concentration calculations were based on actual tumor volume mean at the time of randomization. 50 μL fixed volume was administered. The treatment groups are shown in TABLE 12.
TABLE 12
Figure imgf000323_0001
[001142] Compound 7 and Compound 9 were also administered intratumorally (IT), once weekly for 3 weeks (QWx3). Dose concentration calculations were based on actual tumor volume mean at the time of randomization. 50 pL fixed volume was administered. The treatment groups are shown in TABLE 13. TABLE 13
Group N Dose
6 Vehicle
1
6 Compound 7; 0.3 μM
2
6 Compound 7; 3 μM
3
6 Compound 7; 10 μM
4
6 Compound 7; 30 μM
5
6 Compound 9; 0.3 μM
6
6 Compound 9; 3 μM
7
6 Compound 9; 10 μM
8
6 Compound 9; 30 μM
9
[001143] Experimental design: The cell line used was Capan-2, and the number of cells injected was 5 x 106 cells/mouse. The cell growth media was McCoy's 5A medium with 10% fetal bovine serum (FBS) + 1% penicillin/streptomycin. The cells were raised under 5% CO2 with a split ratio of 1:5. The cells were inoculated subcutaneously in the right flank using an inoculation vehicle of 50% Matrigel and 50% media in 0.1 mL. Subcutaneous tumor sizes were calculated using the following equation: Tumor volume (mm3) = (a x b2/2), where “b” is the smallest diameter and “a” is the largest diameter. The study was initiated when the mean tumor volume was 90-100 mm3. Samples were randomized using random equilibration of tumor volume. Treatment initiation started on day 1 of the dosing schedule shown in TABLE 13 above. Tumor volume and body weight were measured twice weekly, and gross observations were made daily. The study ended on day 77, when mean tumor volume of the vehicle control group reached 694 mm3.
[001144] Tissue collection: No in-study collections occurred. At study end, Day 77, tumors from three mice per group (one each of high, medium, and low tumor volumes) were excised. Tumors were bisected and a wet weight was taken for each piece. One tumor piece was placed in a cryovial, snap frozen in liquid nitrogen, and stored at -80 °C. The remaining tumor piece was fixed in 10% neutral buffered formalin for 48-72 hours before being transferred to 70% ethanol, then paraffin blocked. Paraffin blocks were stored at room temperature.
[001145] Data and statistical analysis: Mean tumor growth inhibition (TGI) was calculated for Day 77 (the final day all groups were on study) utilizing the following formula. Individual student's t-test was calculated for Day 77 using animal study management software, Study Director. P≤0.05 was considered statistically significant.
( X Treated ^ Treated (oay i^)
TGI = 1- 7= X 100%
(A Vehicle Control ( final ) - X Vehicle Control ^ Day [001146] TABLE 14 shows day 77 mean tumor volumes, tumor growth inhibition, and
Student’s t-test.
TABLE 14
Treatment Dose (QWx3) Day 77 group Day 77 Mean Day 77 Student’s t- Tumor Volume test (mm3) ± SEM % TGI
(p value)*
Vehicle 694.4 ± 100.1
1 — -
Compound 7; 0.3 μM
2 561.7 ± 109.6 22.3 0.646
Compound 7; 3 μM 685.6 ± 123.1 1.5 0.750
3
Compound 7; 10 μM
4 468.9 ± 80.4 37.9 0.221
Compound 7; 30 μM 469.9 ± 119.0 37.7 0.329
5
Compound 8; 0.3 μM
6 698.0 ± 31.8 NR 0.504
Compound 8; 3 μM 558.3 ± 77.0 22.9 0.556
7
Compound 8; 10 μM
8 602.4 ± 199.7 15.5 0.901
Compound 8; 30 μM 594.8 ± 68.8 16.7 0.751
9
* p < 0.05 is considered statistically significant
[001147] Conclusions: An efficacy assessment based on tumor growth inhibition demonstrated anti-tumor activity in all but one treatment group. Treatment with Compound 7 10 mM (Group 4) and Compound 7 30 mM (Group 5), resulted in the greatest efficacy, with a TGI of 37.9% and 37.7%, respectively, when compared to the vehicle control group on Day 77. However, statistical significance was not reached with p values of 0.221 and 0.329, respectively.
[001148] Treatment with Compound 7 and Compound 8 were generally tolerated with no appreciable mean body weight loss observed in any group. Slight to mild tumor necrosis was seen in all groups, including the control group. Necrosis is typical for this tumor model and was non-impactful on study outcome. No other notable clinical observations were recorded throughout the study.
[001149] FIG. 7, Panel A shows results of an IVT assay using DNA coding for either wild type K-Ras or G12Y mutated K-Ras and treated with Compound 7 or Compound 8. FIG. 7, Panel B shows the effect of treatment with Compound 7 or Compound 8 on tumor volumes in animals treated with 0 μM, 0.3 μM, 3 μM, 10 μM, or 30 μM of the compounds. FIG. 8 shows the effect of treatment on tumor volumes when animals were treated with vehicle, 0.1 mg/kg, and 0.3 mg/kg of Compound 7.
EXAMPLE 7: Evaluation of compounds in the SHP-77 human small cell lung tumor xenograft model.
[001150] The anti-tumor activities of Compound 7 and Compound 9 as single agents were investigated in the SHP-77 human small cell lung tumor xenograft model, which displays the G12V KRAS mutation target. The significant endpoint was tumor growth inhibition.
[001151] Test system: ICR SCID (IcrTac:ICR-Prkdcscid), physiologically normal mice were inoculated at 6 weeks of age. 25 Female mice were used, and the animals were not replaced during the duration of the study.
[001152] Animal housing and environment: The mice were kept in individually ventilated microisolator cages and were acclimated for at least 5-7 days. The mice were maintained under pathogen-free conditions. Food and water were provided ad libitum. The mice were provided with Teklad Global Diet® 2920x irradiated pellets and autoclaved water. DietGel® 76Awas provided as needed for supplemental nutrition.
[001153] Vehicle mixture-control: The vehicle control used in the study was PBS (pH 7.4) + Invivofectamine® 3.0. 56 μM of complexation buffer was added to 56 pL of PBS (pH 7.4). 113 μL of Invivofectamine 3.0 was then added. The resultant mixture was agitated by vortex, incubated at 50 °C for 30 minutes, and spun by centrifuge briefly to collect the sample. 221 μL of the PBS / Invivofectamine complex was further diluted with 179 pL PBS to obtain a ratio and dilution of Invivofectamine 3.0 / complexation buffer that matched the most concentrated dosing solution (0.3322 mg/mL). The vehicle was a white solution and made fresh for each dosing every day.
[001154] Administration of vehicle control: The vehicle control was administered intratumorally (IT), once weekly for 3 weeks (QWx3). 50 pL fixed volume was administered. [001155] Test articles: Compound 7 and Compound 9 were clear liquids, and stored at -80 °C. The 30 μM and 10 μM groups were white solutions, and the 3 μM and 0.3 μM groups were clear solutions. Compound 7 (5.63 mg/mL) and Compound 9 (4.76 mg/mL) were heated at 80 °C for 10 minutes after thawed to ensure that the PNA was fully denatured. The PNA was then lightly agitated by vortex. An aliquot was removed from each respective test article and each were diluted in PBS (pH 7.4) to obtain 100 μL of a 2.4 mg/mL PNA solution. 100 μL of complexation buffer was added to 100 μL of the PNA solution, to provide a 1.2 mg/mL solution for transfection. 200 μL of Invivofectamine 3.0 was added to obtain a concentration of 0.6 mg/mL. The resultant mixture was agitated by vortex, incubated at 50 °C for 30 minutes, and spun by centrifuge briefly to collect the sample. The Compound 7 / Invivofectamine complex was further diluted with PBS to obtain a solution of 0.3322 mg/mL (Group 3) to deliver a dose of 30 μM/dose in a 50 μL/dose volume. Portions of the Group 3 solution were further diluted in PBS to concentrations of 0.1107 mg/mL (Group 2) to deliver a dose of 10 μM/dose in a 50 μL/dose volume. The Compound 9 / Invivofectamine complex was further diluted with PBS to obtain a solution of 0.2812 mg/mL (Group 5) to deliver a dose of 30 μM/dose in a 50 μL/dose volume. Portions of the Group 5 solution were further diluted in PBS to concentrations of 0.0937 mg/mL (Group 4) to deliver doses of 10 μM/dose in a 50 μL/dose volume. The PNA stock solutions were refrozen within one hour of thawing. Dosing solutions were made fresh on each dosing day.
[001156] Treatment groups: Compound 7 and Compound 9 were administered intratum orally (IT) on days 1, 15, and 18. Dose concentration calculations were based on actual tumor volume mean at the time of randomization. 50 μL fixed volume was administered. The treatment groups are shown in TABLE 15.
TABLE 15
Figure imgf000327_0001
[001157] Experimental design: The cell line used with SHP-77, and the number of cells injected was 1 x 107 cells/mouse. The cell growth media was RPMI medium with 10% heat- inactivated fetal bovine serum + 1% penicillin/streptomycin + glucose 2.5 g/L + sodium pyruvate 0.1 mM + HEPES 1 mM. The cells were grown under 5% CO2 with a split ratio of 1:5. The cells were inoculated subcutaneously in the right flank using an inoculation vehicle of 50% Matrigel and 50% media in 0.1 mL. Subcutaneous tumor sizes were calculated using the following equation: Tumor volume (mm3) = (a x b2/2), where “b” is the smallest diameter and “a” is the largest diameter. The study was initiated when the mean tumor volume was 97-99 mm3. Samples were randomized using random equilibration of tumor volume. Treatment initiation started on day 1 of the dosing schedule shown in TABLE 15 above. Tumor volume and body weight were measured twice weekly, and gross observations were made daily. The study ended on day 24 when the control mean tumor volume was ≥ 2,000 mm3.
[001158] Tissue collection: No in-study collections occurred. At study end (day 24), tumors from three mice per group (one each of high, medium, and low tumor volumes) were excised. Tumors were bisected and a wet weight was taken of each piece. One tumor piece was placed in a cryovial, snap frozen in liquid nitrogen, and stored at -80 °C. The remaining tumor piece was fixed in 10% neutral buffered formalin for 48-72 hours before being transferred to 70% ethanol, then paraffin blocked. Paraffin blocks were stored at room temperature. Frozen tumor samples from Groups 2 and 4 and all paraffin blocks were retained for possible future analysis.
[001159] Data and statistical analysis: Mean tumor growth inhibition (TGI) was calculated for Day 22 (the final day all groups were on study) utilizing the following formula. Individual student's t-test was calculated for Day 22 using animal study management software, Study Director. P ≤0.05 was considered statistically significant.
Figure imgf000328_0001
[001160] TABLE 16 shows day 24 mean tumor volumes, tumor growth inhibition, and
Student’s t-test.
TABLE 16 μM μM μM
Figure imgf000328_0002
* p ≤ 0.05 is considered statistically significant
[001161] Conclusions: An efficacy assessment based on tumor growth inhibition showed anti- tumor activity in groups treated with Compound 9. Treatment with Compound 9, 30 μM/dose (Group 5) showed the highest efficacy, resulting in a TGI of 43.2% on day 24 when compared to the vehicle control group. Treatments with Compound 7 produced unremarkable efficacy, with a TGI of 6.0-11.5% on day 24. Overall, treatment with Compound 9 demonstrated greater efficacy than did treatment with Compound 7. FIG. 9, Panel A shows the effect of Compound 7 and Compound 9 on SHP-77 tumor volume when administered at a dose of 10 μM and 30 μM (IT). FIG. 9, Panel B shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compound 7 and Compound 9. FIG. 10 shows the effect of Compound 7 and Compound 9 on body weight of mice inoculated with SHP-77 cells when administered at a dose of 10 mM and 30 μM (IT). [001162] Treatment with the compounds was generally well tolerated. Mild to marked mean body weight loss was seen in all groups throughout the study, with treated groups exhibiting the greatest weight loss. Body weights did not recover by study end. No significant tumor necrosis was observed across the groups. Notable clinical observations seen in the vehicle control and treatment groups included emaciation and hunched posture, with select mice exhibiting dehydration, change in gait, tremors, and/or hypoactivity.
EXAMPLE 8: Cytotoxicity, cell cycle arrest, and mRNA knock-down of cells treated with RNA Binder (HPAF-II G12D).
[001163] HPAF-II cells were plated in a 24-well plate at a density of 100,000 cells/mL in 2% serum. The following day, PNA compounds of the disclosure were added at 1 μM and 5 μM final concentrations. In control cells, the same volume of water was added. Each compound was tested in duplicate and heated at 80 °C for 10 minutes before use. Cells were grown for 5 days in the presence of the PNA compounds. On day 5, the following analyses were completed: 1) cell viability was tested using an AlamarBlue™ assay; 2) cell cycle arrest was tested using PI staining; 3) mRNA levels of wild type and mutant KRAS were tested using qRT-PCR; and 4) mutant KRAS protein expression was quantified using western blotting.
[001164] FIG. 11, Panel A shows the results of the cell viability assay of HPAF-II cells treated with 1 μM or 5 μM Compound 6 compared to controls (control cells untreated, HPAF-II; cells treated only with the transfection reagent Lipofectamine 2000, HPAF-II Lipo). FIG. 11, Panel B shows cell cycle arrest results of HPAF-II cells treated with 1 μM or 5 μM Compound 6 compared to controls (control cells untreated, Mock; cells treated only with the transfection reagent Lipofectamine 2000, Lipo only).
[001165] FIG. 12, Panel A shows mRNA levels for KRAS alleles treated with Compound 6 as measured by qRT-PCR. FIG. 12, Panel B shows G12D mutant KRAS protein levels when cells were treated with Compound 6 as measured by western blot. The stars and arrows show the temporal offset of mRNA levels and mutant KRAS protein levels when cells were treated with Compound 6 at 1 μM or 5 μM. The data show that a period of 5 days was not long enough to degrade existing mutant protein levels, and selectivity did not translate for Compound 6. Each experiment was replicated in triplicate.
EXAMPLE 9: Cytotoxicity, cell cycle arrest, and mRNA knock-down of cells treated with RNA Binder (Capan2 G12V).
[001166] Capan2 cells were plated in 24-well plates at 100,000 cells/mL in 2% serum. The following day, PNA compounds were added at 1 μM and 5 μM final concentrations. In control cells, the same volume of water was added to the wells. Each compound was tested in triplicate and heated at 80 °C for 10 minutes before use. The cells were grown for 5 days in the presence of the compounds. On day 5, the following analyses were completed: 1) cell viability was tested using an AlamarBlue assay; 2) cell cycle arrest was tested using PI staining; 3) mRNA levels of wild type and mutant KRAS were tested using qRT-PCR; and 4) mutant K-Ras protein expression was quantified using western blotting.
[001167] FIG. 13, Panel A shows the results of the cell viability assay of Capan2 cells treated with 1 μM or 5 μM Compound 7 compared to controls (control cell untreated, Capan2; cells treated only with the transfection reagent Lipofectamine 2000, Capan2 Lipo). FIG. 13, Panel B shows cell cycle arrest results of Capan2 cells treated with 1 μM or 5 μM Compound 7 compared to controls (control cell untreated, Mock; cells treated only with the transfection reagent Lipofectamine 2000, Lipo only).
[001168] FIG. 14, Panel A shows mRNA levels for KRAS alleles treated with Compound 7 as measured by qRT-PCR. FIG. 14, Panel B shows G12V mutant K-ras protein levels when cells were treated with Compound 7 as measured by western blot. The arrows show the temporal offset of mRNA levels and mutant K-ras protein levels when cells were treated with Compound 7 at 1 μM or 5 μM.
EXAMPLE 10: Effect of Compound 51 on tumor volume
[001169] The effect of Compounds 76 and 90 on tumor volume were tested in HPAF-II G12D xenograft model using the experimental method described in EXAMPLE 5. The treatment groups are shown in TABLE 17 below. TABLE 17 μM μM
Figure imgf000331_0001
[001170] FIG. 15, Panel A shows results of an IVT assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compound 51. FIG. 15, Panel B shows the effect of treatment with Compound 51 on tumor volume in animals treated with control (PBS buffer); control (glucose buffer); 30 μM Compound 51 (PBS); 10 mg/kg Compound 51 (PBS);
30 μM Compound 51 (glucose buffer); or 10 mg/kg Compound 51 (glucose buffer). The arrow shows that treatment with Compound 51 in glucose buffer at a concentration of 10 mg/kg had the greatest effect on tumor volume.
EXAMPLE 11: Effect of Compounds 76 and 90 on tumor volume.
[001171] The effect of Compounds 76 and 90 on tumor volume were tested in SHP77 G12V xenograft model using the experimental method described in EXAMPLE 5. The treatment groups are shown in TABLE 18 below. μM μM μM μM
Figure imgf000331_0002
[001172] FIG. 16, Panel A shows results of an SHP77 IVT assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compound 76 or Compound 90. FIG. 16, Panel B shows the effect of treatment with Compound 76 or Compound 90 on tumor volume in animals treated with control (PBS vehicle); Compound 76 at 60 μM/dose; Compound 76 at 120 μM/dose; or Compound 90 at 120 μM/dose.
[001173] The effect of Compounds 76 and 90 on tumor volume were tested in a Capan2 G12V xenograft model using the experimental method described in EXAMPLE 5. The treatment groups are shown in TABLE 19 below.
TABLE 19
Figure imgf000332_0001
[001174] FIG. 17, Panel A shows results of a Capan2 IVT assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compound 76 or Compound 90. FIG. 17, Panel B shows the effect of treatment with Compound 76 or Compound 90 on tumor volume in animals treated with glucose control; Compound 76 at 30 mg/kg; Compound 90 at 5 mg/kg; and Compound 90 at 30 mg/kg.
EXAMPLE 12: Effect of compounds on KRAS downstream signaling.
[001175] Tumors were obtained from the studies described in EXAMPLE 5, EXAMPLE 6, and EXAMPLE 7. Protein lysates were spotted in triplicate onto nitrocellulose backed slides in technical triplicates as well as analyte control (SW620 and THP1) and bovine serum albumin
(BSA) standards. Nitrocellulose slides were then stained using multiple antibodies according to the Theralink Technologies ® RPPA staining protocol. Protein detection was amplified via horseradish peroxidase mediated biotinyl tyramide deposition and visualized using a fluorescent probe. For total protein determination, a nitrocellulose slide was treated with 1% sodium hydroxide, incubated in a destain solution (7% acetic acid; 30% methanol), and a 0.2% Fast green solution was applied. Images of stained RPPA and Fast green stained slides were captured on an InnoScan® 710-AL. Individual spots were detected using the InnoScan® software program. Total protein normalized data was plotted in GraphPad 9.1.0.
[001176] FIG. 18A, Panels A-D show that mice with HPAF-II tumors treated with Compounds 5 and 6 according to EXAMPLE 5 and sacrificed on days 25-30 post-first dose exhibited decreased KRAS downstream signaling between 11 and 16 days post-last dose. Panel A shows G12D mutated K-Ras (RasG12D) relative to wild type K-Ras, Panel B shows G12V mutated K- Ras (RasG12V) relative to wild type K-Ras, Panel C shows P90RSK (via phospho-P90RSK T359/S363), and Panel D shows RSK3 (via phospho-RSK3 T356/S360).
[001177] FIG. 18B, Panels E-H show that mice with HPAF-II tumors treated with Compounds 5 and 6 according to EXAMPLE 5 and sacrificed on days 25-30 post-first dose exhibited decreased KRAS downstream signaling between 11 and 16 days post-last dose. Panel E shows MEK (via phospho-MEK1/2 S217/S221), Panel F shows ERK (via phospho-ERK T202/Y204), Panel G shows MSK1 (via phospho-MSKl S360), and Panel H shows CREB (via phospho- CREB SI 33).
[001178] FIG. 19A, Panels A-D show the level of decreased KRAS signaling observed in SHP77 tumors treated with Compound 7 and Compound 9 in EXAMPLE 7. Panel A shows G12D mutated K-Ras (RasG12D) relative to wild type K-Ras, Panel B shows G12V mutated K- Ras (RasG12V) relative to wild type K-Ras, Panel C shows P90RSK (via phospho-P90RSK T359/S363), and Panel D shows RSK3 (via phospho-RSK3 T356/S360).
[001179] FIG. 19B, Panels E-H show the level of decreased KRAS signaling observed in SHP77 tumors treated with Compound 7 and Compound 9 in EXAMPLE 7. Panel E shows MEK (via phospho-MEKl/2 S217/S221), Panel F shows ERK (via phospho-ERK T202/Y204), Panel G shows MSK1 (via phospho-MSKl S360), and Panel H shows CREB (via phospho- CREB SI 33).
[001180] FIG. 20, Panels A-F show that no cell signaling differences were observed in KRAS downstream signaling pathways at 43 days post-first injection in Capan-2 xenograft tumors treated with Compound 7 or Compound 8 according to EXAMPLE 6. Panel A shows G12D mutated K-Ras (RasG12D), Panel B shows G12V mutated K-Ras (RasG12V), Panel C shows G12V mutated K-Ras (RasG12V) relative to wild type K-Ras, Panel D shows CREB (via phospho-CREB S133), Panel E shows MSK1 (via phospho-MSK1 S360), and Panel F shows P90RSK (via phospho-P90RSK T359/S363).
[001181] FIG. 21, Panels A-E show that no cell signaling differences were observed in KRAS downstream signaling pathways at 43 days post-first injection in Capan-2 xenograft tumors treated with Compound 7 or Compound 8 according to EXAMPLE 6. Panel A shows G12D mutated K-Ras (RasG12D) relative to wild type K-Ras, Panel B shows wild type K-Ras, Panel C shows MEK (via phospho-MEKl/2 S217/S221), Panel D shows ERK (via phospho-ERK T202/Y204), and Panel E shows RSK3 (via phospho-RSK3 T356/S360).
EXAMPLE 13: mRNA Knockdown study of KRAS RNA binders.
[001182] A427 (lung), HPAF-II (pancreas), and PANC1 (pancreas) cell lines were plated in 24- well plates with 2% FBA media. The cells were transfected using 6 mM of Endo-porter with or without Compound 6 (1 mM final concentration). After 3 days in culture, KRAS mRNA levels for wild type and mutated alleles (G12D) were analyzed by qPCR.
[001183] FIG. 22, Panel A shows changes in mRNA levels of KRAS in A427 cells treated with control, Endo-Porter only, and Endo-Porter and Compound 6. FIG. 22, Panel B shows changes in mRNA levels of KRAS in HPAF-II cells treated with control, Endo-Porter only, and Endo- Porter and Compound 6. FIG. 22, Panel C shows changes in mRNA levels of KRAS in PANC1 cells treated with control, Endo-Porter only, and Endo-Porter and Compound 6.
EXAMPLE 14: In vitro transcription and translation assay using selected G12D, G12V and G12C KRAS binding compounds of the disclosure.
[001184] An In vitro transcription and translation assay was performed using a PURExpress® In Vitro Protein Synthesis Kit following the instructional protocol with minor modifications. Briefly, a DNA coding for either wild type K-Ras or mutated K-Ras (G12D, G12V and G12C) was amplified by PCR. 100 ng was used as a template in the cell-free transcription/ translation system in presence of compounds of the disclosure at final concentrations of 1 μM. The reactions were incubated at 37 °C for 1 hour. Then, 5 μL of each reaction was analyzed by SDS- PAGE using a K-Ras antibody (dilution 1:5000). AHRP conjugate anti -rabbit secondary antibody (1 : 10,000) was used to visualize proteins using SuperSignal™ West Pico Plus Chemiluminescent Substrate. Protein bands were quantified using iBright™ Analysis Software. RAS protein levels were normalized to the control reaction (no PNA in IVT reaction). For PNAs targeting the DNA, PNA compounds were incubated for 30 minutes at 37 °C with the DNA template before adding IVT kit components.
[001185] FIG. 23, Panel A shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 5, 6, and 11-17. FIG. 23, Panel B shows the results of an IVT assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compounds 7-9 and 18-29. FIG. 23, Panel C shows the results of an IVT assay using DNA coding for either wild type K-Ras or G12C mutated K-Ras and treated with Compounds 30-42. Compounds 5 and 6 (data not shown) showed the strongest specific effect for the G12D template. Cell line screening showed that wild type and mutant KRAS mRNA levels dropped by about 80% after lipofectamine transfection of Compound 7 at 1 μM. Decreased cell number in Phase S was observed, but no effect was observed on cell cycle using an endo-porter method.
[001186] FIG. 24 shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12D mutated K-Ras and treated with Compounds 43-69. The tested compounds had IC50 values greater than 10 μM. No changes in KRAS Protein levels of cell cycle arrest were observed upon addition of the compounds.
[001187] FIG. 25, Panel A shows the results of an in vitro transcription and translation (IVT) assay using DNA coding for either wild type K-Ras or G12V mutated K-Ras and treated with Compounds 70-95. FIG. 25, Panel B shows the results of an IVT assay using DNA coding for either wild type K-Ras or G12C mutated K-Ras and treated with Compounds 96-110. The data show that the IC50 values for the tested compounds were greater than 10 μM. The data also show that KRAS protein levels and cell cycle arrest did not change after addition of the DNA binders. [001188] Compounds 51, 52, 62, 63, and 69 (DNA binder G12D); and Compounds 71, 75, 76, 89, and 92 (DNA binder G12V) exhibited the highest efficacy against KRAS mutants.
EXAMPLE 15: In vitro transcription and translation assay using compounds 204-220. [001189] An in vitro transcription and translation assay (IVT) was performed using a PURExpress™ In Vitro Protein Synthesis Kit (NEB #E6800) following the manufacturer protocol with minor modification. Briefly, a RNA template coding for either wild type K-Ras or mutated K-Ras (G12D) was generated from DNA via in vitro transcription (Thermo Fisher, AMB13345). 100 ng of the purified RNA was used in the IVT system with compounds 204-220 added at a concentration of either 0.5 or 0.25 μM. After pre-incubation at 37 °C for 30 minutes, the in vitro protein synthesis kit components were added, and the reactions were incubated at 37 °C for 30 minutes on a thermocycler. Finally, 1 μL protein sample for each reaction was analyzed using a fully automated western blot system (Simple Western™ platform) using a specific antibody for K-Ras (dilution 1 : 10000, Thermo # 703345), which was detected by a chemiluminescent anti-Rabbit detection module (Bio-techne DM-001). K-ras protein level was normalized to control reaction (no PNA in IVT reaction). FIG. 26, Panel A shows relative K- Ras protein densities observed for compounds dosed at 0.5 μM. FIG. 26, Panel B shows relative K-Ras protein densities observed for compounds dosed at 0.25 μM.
[001190] While preferred embodiments of the present invention have been shown and/or described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS What is claimed is:
1. A compound compri sing :
1) a pharmacophore, wherein the pharmacophore is a region that comprises a structure that interferes with expression of a cancer-causing protein; and
2) connected to the pharmacophore, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000337_0001
ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
2. The compound of claim 1, wherein each of R1, R3, and R4 is hydrogen; and R2 is NH or
N(PgN).
3. The compound of claim 1 or claim 2, wherein R5 is linear alkyl.
4. The compound of claim 1 or claim 2, wherein R5 is methyl
5. The compound of any one of claims 1-4, wherein n is 3.
6. The compound of any one of claims 1-4, wherein n is 4.
7. The compound of claim 1, further comprising a first chemical moiety attached to the oligomeric structure, wherein the oligomeric structure, the first chemical moiety, and the pharmacophore form:
Figure imgf000338_0001
, wherein:
E1 is the first chemical moiety, and E2 is the pharmacophore; or E1 is the pharmacophore, and E2 is the first chemical moiety; and p is an integer that is 1-100.
8. The compound of claim 7, wherein p is 6.
9. The compound of claim 7, wherein p is 7.
10. The compound of claim 7, wherein p is 8.
11. The compound of any one of claims 7-10, wherein E1 is the first chemical moiety, wherein the first chemical moiety is hydrogen, acyl, a group that together with the nitrogen atom to which E1 is bound forms a carbamate, a probe, a metal chelator, or an imaging agent; and E2 is the pharmacophore.
12. The compound of any one of claims 7-10, wherein E1 is the pharmacophore; and E2 is the first chemical moiety, wherein the first chemical moiety is OH, OMe, NH 2, a probe, a metal chelator, or an imaging agent.
13. The compound of any one of claims 7-10, wherein E1 is hydrogen and E2 is the pharmacophore.
14. The compound of any one of claims 1-13, wherein the cancer-causing protein is mutant K- ras.
15. The compound of any one of claims 1-14, wherein the cancer-causing protein is G12D K- ras.
16. The compound of any one of claims 1-14, wherein the cancer-causing protein is G12C K - ras.
17. The compound of any one of claims 1-14, wherein the cancer-causing protein is G12V K - ras.
18. The compound of any one of claims 1-13, wherein pharmacophore binds to a nucleic acid sequence encoding a cancer gene.
19. The compound of any one of claims 1-13, wherein pharmacophore binds to a mRNA sequence transcripted from a cancer gene.
20. The compound of any one of claims 1-13, wherein pharmacophore binds to a DNA sequence encoding a cancer gene.
21. The compound of any one of claims 18-20, wherein the cancer gene is non-wild type KRAS.
22. The compound of any one of claims 18-21, wherein the cancer gene is G12D KRAS.
23. The compound of any one of claims 18-21, wherein the cancer gene is G12C KRAS.
24. The compound of any one of claims 18-21, wherein the cancer gene is G12V KRAS.
25. The compound of any one of claims 1-24, wherein the pharmacophore is an oligonucleotide or oligonucleotide analogue.
26. The compound of any one of claims 1-24, wherein the pharmacophore is a peptide nucleic acid.
27. The compound of claim 1, wherein the compound is:
Figure imgf000340_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L3 is a linker group or absent;
N-Terminus is H, acyl, a group that together with the nitrogen atom to which the N-Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
28. The compound of claim 27, wherein L3 is absent.
29. The compound of claim 27 or claim 28, wherein N-terminus is H.
30. The compound of any one of claims 27-29, wherein C-Terminus is NH2
31. The compound of any one of claims 27-30, wherein each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen.
32. The compound of claim 1, wherein the compound is:
Figure imgf000341_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L4 is a linker group or absent; N-Terminus is H, acyl, a group that together with the nitrogen atom to which the N-Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
33. The compound of claim 32, wherein L4 is absent.
34. The compound of claim 32 or claim 33, wherein N-Terminus is H.
35. The compound of any one of claims 32-34, wherein C-Terminus is NH2.
36. The compound of any one of claims 32-35, wherein each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen.
37. A compound comprising a structure that is:
Figure imgf000342_0001
wherein: the number of units with variables defined independently is at least 11;
N-Terminus is H, acyl, a group that together with the nitrogen atom to which the A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, O-alkyl, a peptide sequence, or NH2
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent;
L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof, wherein the compound interferes with expression of a cancer-causing protein.
38. The compound of claim 37, wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27.
39. The compound of claim 37 or claim 38, wherein N-Terminus is H and C-Terminus is Nth.
40. The compound of any one of claims 37-39, wherein each R1 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
41. The compound of any one of claims 37-39, wherein at least one iteration of R1 is hydroxylmethyl.
42. The compound of any one of claims 37-39, wherein at least half the iterations of R1 are hydroxylmethyl and the other iterations of R1 are H.
43. The compound of any one of claims 37-42, wherein each of L1, L2, L3, L4, L5, and L6 is absent.
44. The compound of any one of claims 37-43, wherein SOL1 and SOL2 are absent.
45. The compound of any one of claims 37-44, wherein one of PEP1 and PEP2 is a peptide sequence that is a nuclear localization sequence and the other is absent.
46. The compound of any one of claims 37-45, wherein one of PEP1 and PEP2 is -Pro-Lys-Lys- Lys-Arg-Lys-Val- (SEQ ID NO: 1).
47. The compound of any one of claims 37-45, wherein one of PEP1 and PEP2 is -Pro-Ala-Ala- Lys-Arg-Val-Lys-Leu-Asp (SEQ ID NO: 2).
48. The compound of any one of claims 37-43, wherein PEP1 and PEP2 are absent.
49. The compound of any one of claims 37-43, wherein SOLI is the water-solubilizing group and SOL2 is absent.
50. The compound of any one of claims 37-43, wherein each of LI, L2, L3, L4, L5, L6, PEP1, PEP2, and SOL2 is absent, and SOL1 is the water-solubilizing group.
51. The compound of any one of claims 37-43, 49, and 50, wherein the water-solubilizing group is a group that contains multiple positive charges at physiological pH.
52. The compound of any one of claims 37-43 and 49-51, wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000344_0001
R1a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is alkyl or O-alkyl, any of which is unsubstituted or substituted; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-100.
53. The compound of claim 52, wherein p is 5, 6, 7, or 8.
54. The compound of claim 52, wherein p is 7.
55. The compound of any one of claims 37-43 and 49-54, wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000344_0002
wherein p is an integer that is 5, 6, 7, or 8.
56. The compound of any one of claims 37-43 and 49-54, wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000345_0001
wherein p is an integer that is 5, 6, 7, or 8.
57. The compound of claim 55 or claim 56, wherein p is 7.
58. The compound of any one of claims 37-57, wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
59. The compound of any one of claims 37-58, wherein the heterocycles of the R2 groups are each independently:
Figure imgf000345_0002
60. The compound of any one of claims 37-58, wherein each R2 group in the structure is independently:
Figure imgf000346_0001
61. The compound of any one of claims 37-60, wherein the number of units with variables defined independently is 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000346_0002
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000346_0003
a third unit is present, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000346_0004
a fourth unit is present, and in the fourth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000347_0001
a fifth unit is present, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000347_0002
a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000347_0003
a seventh unit is present, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000347_0004
an eighth unit is present, and in the eighth unit:
Figure imgf000347_0005
a ninth unit is present, and in the ninth unit:
Figure imgf000348_0005
a tenth unit is present, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000348_0001
an eleventh unit is present, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000348_0002
a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000348_0003
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000348_0004
a fourteenth unit is present, and in the fourteenth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000349_0001
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000349_0002
a sixteenth unit is present, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000349_0003
and a seventeenth unit is present or absent, and in the seventeenth unit: 1
Figure imgf000349_0004
62. The compound of any one of claims 37-60, wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, or 17, wherein: a first unit is present or absent, and in the first unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000350_0001
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000350_0002
O a third unit is present or absent, and in the third unit:
R is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000350_0003
a fourth unit is present or absent, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000350_0004
a fifth unit is present, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000350_0005
O a sixth unit is present, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000350_0006
a seventh unit is present, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000351_0001
an eighth unit is present, and in the eighth unit: 1
Figure imgf000351_0004
a ninth unit is present, and in the ninth unit:
Figure imgf000351_0002
a tenth unit is present, and in the tenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000351_0003
an eleventh unit is present, and in the eleventh unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000352_0001
O a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000352_0002
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000352_0003
a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000352_0004
O a fifteenth unit is present or absent, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000352_0005
a sixteenth unit is present or absent, and in the sixteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000352_0006
and a seventeenth unit is present or absent, and in the seventeenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000353_0001
63. The compound of any one of claims 37-60, wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, wherein: a first unit is present or absent, and in the first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000353_0002
a second unit is present or absent, and in the second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000353_0003
a third unit is present or absent, and in the third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000353_0004
a fourth unit is present or absent, and in the fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is
Figure imgf000353_0005
a fifth unit is present or absent, and in the fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is
Figure imgf000354_0001
a sixth unit is present or absent, and in the sixth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000354_0002
a seventh unit is present or absent, and in the seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000354_0003
an eighth unit is present or absent, and in the eighth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000354_0004
a ninth unit is present or absent, and in the ninth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl; and R2 is
Figure imgf000354_0005
a tenth unit is present or absent, and in the tenth unit: R1 is H, -CH2OH, or 4-guanidinobut-11yl;
Figure imgf000355_0001
an eleventh unit is present or absent, and in the eleventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-l-yl;
Figure imgf000355_0002
a twelfth unit is present, and in the twelfth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000355_0003
a thirteenth unit is present, and in the thirteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000355_0004
a fourteenth unit is present, and in the fourteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000355_0005
a fifteenth unit is present, and in the fifteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000355_0006
a sixteenth unit is present, and in the sixteenth unit:
Figure imgf000356_0001
a seventeenth unit is present, and in the seventeenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000356_0002
O an eighteenth unit is present, and in the eighteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000356_0003
a nineteenth unit is present, and in the nineteenth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000356_0004
a twentieth unit is present, and in the twentieth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000356_0005
a twenty-first unit is present, and in the twenty -first unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000357_0001
a twenty-second unit is present or absent, and in the twenty-second unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000357_0002
a twenty-third unit is present or absent, and in the twenty-third unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000357_0003
a twenty-fourth unit is present or absent, and in the twenty-fourth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000357_0004
a twenty-fifth unit is present or absent, and in the twenty -fifth unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000357_0005
a twenty-sixth unit is present or absent, and in the twenty-sixth unit: R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000358_0001
a twenty-seventh unit is present or absent, and in the twenty-seventh unit:
R1 is H, -CH2OH, or 4-guanidinobut-1-yl;
Figure imgf000358_0002
64. The compound of any one of claims 37-63, wherein the compound binds to a nucleic acid sequence encoding the cancer-causing protein.
65. The compound of any one of claims 37-64, wherein the cancer-causing protein is mutant K- ras.
66. The compound of any one of claims 37-64, wherein the cancer-causing protein is G12D K- ras.
67. The compound of any one of claims 37-64, wherein the cancer-causing protein is G12C K- ras.
68. The compound of any one of claims 37-64, wherein the cancer-causing protein is G12V K- ras.
69. The compound of claim 65, wherein the compound binds to the nucleic acid sequence encoding the mutant K-ras by interactions between the heterocycles of the R2 groups and nucleobases of the nucleic acid sequence.
70. The compound of claim 69, wherein the nucleic acid sequence is a mRNA sequence.
71. The compound of claim 69, wherein the nucleic acid sequence is a DNA sequence.
72. A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of any one of claims 37-63.
73. The method of claim 72, wherein the condition is cancer.
74. The method of claim 72 or claim 73, wherein the condition is associated with a non-wild type gene in the subject, wherein the non-wild type gene differs from a corresponding wild type gene in a single nucleotide polymorphism.
75. The method of claim 74, wherein the non-wild type gene is non-wild type KRAS.
76. The method of claim 75, wherein the non-wild type KRAS gene is G12D KRAS.
77. The method of claim 75, wherein the non-wild type KRAS gene is G12C KRAS.
78. The method of claim 75, wherein the non-wild type KRAS gene is G12V KRAS.
79. The method of any one of claims 72-75, wherein the condition is pancreatic ductal adenocarcinoma, lung adenocarcinoma, multiple myeloma, pancreatic ductal adenocarcinoma, or multiple myeloma.
80. The method of any one of claims 72-79, wherein the subject is human.
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