WO2022235889A1 - Conjugués liés à hsp90 et formulations de ceux-ci - Google Patents

Conjugués liés à hsp90 et formulations de ceux-ci Download PDF

Info

Publication number
WO2022235889A1
WO2022235889A1 PCT/US2022/027805 US2022027805W WO2022235889A1 WO 2022235889 A1 WO2022235889 A1 WO 2022235889A1 US 2022027805 W US2022027805 W US 2022027805W WO 2022235889 A1 WO2022235889 A1 WO 2022235889A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
conjugates
cell
cancer
conjugate
Prior art date
Application number
PCT/US2022/027805
Other languages
English (en)
Inventor
Mark T. Bilodeau
Ashis K. Saha
Original Assignee
Tva (Abc), Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tva (Abc), Llc filed Critical Tva (Abc), Llc
Publication of WO2022235889A1 publication Critical patent/WO2022235889A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the disclosure generally relates to the field of therapeutic compounds.
  • the disclosure relates to the use of compounds targeting heat shock proteins including heat shock protein 90 (HSP90), e.g., for treating cancer.
  • HSP90 heat shock protein 90
  • HSP90 Heat shock protein 90
  • HSP90 is an intracellular chaperone protein that assists protein folding, stabilizes proteins against heat stress, and aids in protein degradation. It is upregulated in many types of cancer. Many Hsp90 client proteins are over-expressed in cancer, often in mutated forms, and are responsible for unrestricted cancer cell proliferation and survival. HSP90 is activated in cancer tissues and latent in normal tissues. HSP90 derived from tumour cells has higher binding affinity to HSP90 inhibitors than the latent form in normal cells, allowing specific targeting of HSP90 inhibitors to tumour cells with litle inhibition of HSP90 function in normal cells. Further, HSP90 has also been recently identified as an important extracellular mediator for tumour invasion , Therefore, HSP90 is considered a major therapeutic target for anticancer drug development. There is a need in the art for developing therapeutic compounds that binds to HSP90.
  • the present application provides a conjugate comprising an active agent coupled to an HSP90 targeting moiety by a linker and a pharmaceutical composition comprising such a conjugate.
  • the conjugate inhibits of the activity or function of a target protein in cells.
  • the conjugates induces degradatiou of the target protein.
  • the active agent is a BET inhibitor such as a BRD4 inhibitor.
  • Fig. 1 shows BRD4 protein levels (corrected for GAPDH) in LS174T cells mearued 24 hours after treatment with Compound 24.
  • Fig. 2 shows BRD4 protein levels (corrected for GAPDH) in MV4-11 cells measured 24 hours after treatment with Compound 22.
  • HSP90 targeting conjugates comprising an active agent and novel particles comprising such conjugates. Such targeting can, for example, improve the amount of active agent at a site and decrease active agent toxicity to the subject.
  • HSP90 targeting conjugates of the present disclosure have deep and rapid tumor penetration and do not require receptor internalization. High accumulation and long retention time of HSP90 targeting conjugates enable the use of cytotoxic and non-cytotoxic payloads, such as chemotherapeutic agents, kinase inhibitors, or imirmno-oneology modulators.
  • toxicity refers to the capacity of a substance or composition to be harmful or poisonous to a cell, tissue organism or cellular environment.
  • Low toxicity refers to a reduced capacity of a substance or composition to be harmful or poisonous to a cell, tissue organism or cellular environment. Such reduced or low toxicity may be relative to a standard measure, relative to a treatment or relati ve to the absence of a treatment.
  • Toxicity may further be measured relative to a subject’s weight loss where weight loss over 15%, over 20% or over 30% of the body weight is indicative of toxicity.
  • Other metrics of toxicity may also be measured such as patient presentation metrics including lethargy and general malaiase.
  • Neutropenia or thrombopenia may also be metrics of toxicity .
  • Pharmacologic indicators of toxicity include elevated AST/ALT levels, neurotoxicity, kidney damage, GI damage and the like.
  • the conjugates are released after administration of the particles.
  • the targeted drug con j ugates utilize active molecular targeting in combination with enhanced permeability and retention effect (EPR) and improved overall biodistribution of the particles to provide greater efficacy and tolerability as compared to administration of targeted particles or encapsulated untargeted drug.
  • EPR enhanced permeability and retention effect
  • the toxicity of a conjugate containing an H8P90 targeting moiety linked to an active agent for cells that do not overexpress HSP90 is predicted to be decreased compared to the toxicity of the active agent alone. Without committing to any particular theory, applicants belie ve that this feature is because the ability of the conjugated active agent to be retained in a normal cell is decreased relative to a tumor cell .
  • Conjugates include an active agent or prodrug thereof attached to a targeting moiety, e.g., a molecule that can bind to H8P90, by a linker.
  • the conjugates can be a conjugate between a single active agent and a single targeting moiety, e.g., a conjugate having the structure X-Y-Z where X is the targeting moiety, Y is the linker, and Z is the active agent.
  • the conjugate contains more than one targeting moiety, more than one linker, more than one active agent, or any combination thereof.
  • the conjugate can have any number of targeting moieties, linkers, and active agents.
  • the conjugate can have the structure X-Y-Z-Y-X, (X-Y) n -Z, X-(Y-Z) n , X n -Y-Z, X-Y- Z n , (X-Y-Z) n , (X-Y-Z-Y) n -Z, where X is a targeting moiety, Y is a linker, Z is an active agent, and n is an integer between 1 and 50, between 2 and 20, for example, between 1 and 5.
  • Each occurrence of X, Y, and Z can be the same or different, e.g., the conjugate can contain more than one type of targeting moiety, more than one type of linker, and/or more than one type of active agent.
  • the conjugate can contain more than one targeting moiety attached to a single active agent.
  • the conjugate can include an active agent with multiple targeting moieties each attached via a different linker.
  • the conjugate can have the structure X-Y-Z-Y-X where each X is a targeting moiety that may be the same or different, each Y is a linker that may be the same or different, and Z is the active agent.
  • the conj ugate can contain more than one active agent attached to a single targeting moiety.
  • the conjugate can include a targeting moiety with multiple active agents each attached via a different linker.
  • the conjugate can have the structure Z-Y-X-Y-Z where X is the targeting moiety, each Y is a linker that may be the same or different, and each Z is an active agent that may be the same or different.
  • a conjugate as described herein contains at least one active agent (a first active agent).
  • the conjugate can contain more than one active agent, that can be the same or different from the first active agent.
  • the active agent can be a therapeutic, prophylactic, diagnostic, or nutritional agent.
  • a variety of acti ve agents are known in the art and may be used in the conjugates described herein.
  • the active agent can be a protein or peptide, small molecule, nucleic acid or nucleic acid molecule, lipid, sugar, glycolipid, glycoprotein, lipoprotein, or combination thereof,
  • the active agent is an antigen, an adjuvant, radioactive, an imaging agent (e.g., a fluorescent moiety) or a polynucleotide.
  • the active agent is an organ ometall ic compound .
  • the active agent of the conjugate comprises a predetermined molar weight percentage from about 1% to about 10%, or about 10% to about 20%, or about 20% to about 30%, or about 30% to about 40%, or about 40% to about 50%, or about 50% to about 60%, or about 60% to about 70%, or about 70% to about 80%, or about 80% to about 90%, or about 90% to about 99% such that the sum of the molar weight percentages of the components of the conjugate is 100%.
  • the amount of active agent(s) of the conjugate may also be expressed in terms of proportion to the targeting ligand(s).
  • the present teachings provide a ratio of active agent to ligand of about 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5:1, 4: 1, 3:1, 2:1, 1: 1, 1:2, 1 :3, 1 :4; 1:5, 1:6, 1:7, 1 :8, 1 :9, or 1:10.
  • the active agent can be a cancer therapeutic.
  • Cancer therapeutics include, for example, death receptor agonists such as the TNF-related apoptosis-inducing ligand (TRAIL,) or Fas ligand or any ligand or antibody that binds or activates a death receptor or otherwise induces apoptosis.
  • TRAIL TNF-related apoptosis-inducing ligand
  • Suitable death receptors include, but are not limited to, TNFR1, Fas, DR3, DR4, DR5, DR6, LT ⁇ R and combinations thereof.
  • Cancer therapeutics such as chemotherapeutic agents, cytokines, chemokines, and radiation therapy agents can be used as active agents.
  • Chemotherapeutic agents include, for example, alkylating agents, antimetabolites, anth racy clines. plant alkaloids, topoisomerase inhibitors, and other antitumor agents. Such agents typically affect cell division or DNA synthesis and function.
  • Additional examples of therapeutics that can be used as active agents include monoclonal antibodies and the tyrosine kinase inhibitors e.g. imatimb mesylate, which directly targets a molecular abnormality in certain types of cancer (e.g., chronic myelogenous leukemia, gastrointestinal stromal tumors).
  • Chemotherapeutic agents include, but arc not limited to cispiatin, carboplatin, oxaliplatin, mechlorethaminc, cyclophosphamide, chlorambucil, vincristine, vinblastine, vinoreibine, vindesine, taxol and derivatives thereof, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, epipodophyllotoxins, trastuzumab, cetuximab, and rituximab, bevacizumab, and combinations thereof. Any of these may be used as an active agent in a conjugate.
  • the small molecule active agents used in this disclosure include cytotoxic compounds (e.g., broad spectrum), angiogenesis inhibitors, cell cycle progression inhibitors, PBK/m- TOR/AKT pathway inhibitors, MAPK signaling pathway inhibitors, kinase inhibitors, protein chaperones inhibitors, HD AC inhibitors, PARP inhibitors, Wnt'Hedgehog signaling pathway inhibitors, RNA polymerase inhibitors and proteasome inhibitors.
  • the small molecule active agents in some embodiments the active agent is an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof.
  • Broad spectrum cytotoxins include, but are not limited to, DNA-binding or alkylating drags, microtubule stabilizing and destabilizing agents, platinum compounds, and topoisomerase I or II inhibitors.
  • Exemplary DNA-binding or alkylating drugs include, CC-1065 and its analogs, anthracyclines (doxorubicin, epirubicin, idarubicin, daunorubicin) and its analogs, alkylating agents, such as ealicheamicins, dactinomyeines, mitromycines, pyrrolobenzodiazepines, and the like.
  • doxorubicin analogs include nemorubicin metabolite or analog drug moiety disclosed in US 20140227299 to Cohen et ah, the contents of which are incorporated herein by reference in their entirety,
  • Exemplary CC-1065 analogs include duocarmycin SA, duocannycin CE duocarmycin C2, duocarmycin B2, DU-86, KW-2189, bizelesin, seco-adozelesin, and those described in U.S, Patent Nos.
  • Doxorubicin and its analogs include PNU- 159682 and those described in U.S, Patent No.6, 630, 579 and nemorubicin metabolite or analog drugs disclosed in US 20140227299 to Cohen et al, the contents of which are incorporated herein by reference in their entirety.
  • Calicheamicins include those described in U.S. Patent Nos. 5,714,586 and 5,739,116.
  • Duocarmycins include those described in U.S. Patent Nos.5,070,092; 5,101,038; 5,187,186; 6,548,530; 6,660,742; and 7,553,816 B2; and Li et al, Tet Letts,, 50:2932 - 2.935 (2009).
  • Pyrrolobenzodiazepines include SG2.057 and those described in Denny, Exp. Opin.
  • microtubule stabilizing and destabilizing agents include taxane compounds, such as paclitaxel, docetaxel, cabazitaxel; maytansinoids, auri statins and analogs thereof, tubulysin A and B derivatives, vinca alkaloid derivatives, epothilones, PM060184 and cryptophyeins.
  • Exemplary maytansinoids or maytansinoid analogs include maytansinol and maytansinol analogs, maytansine or DM-1 and DM-4 are those described in U.S. Patent Nos. 5,208,020; 5,416,064; 6,333.410; 6,441,163; 6,716,821; RE39151 and 7,276,497.
  • the cytotoxic agent is a maytansinoid, another group of anti-tubulin agents (ImmunoGen, Inc.; see also Chari et al,, 1992, Cancer Res. 52: 127-131), maytansinoids or maytansinoid analogs.
  • Suitable maytansinoids include maytansinol and maytansinol analogs.
  • Suitable maytansinoids arc disclosed in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; 4,362,663; 4,364,866; 4,450,254; 4,322,348; 4,371,533; 6,333,410; 5,475,092; 5,585,499; and 5,846,545.
  • Exemplary ' auristatins include auristatin E (also known as a derivative of dolastatin-10), auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin.
  • Suitable auristatins are also described in U.S. Publication Nos. 2003/0083263, 2011/0020343, and 2011/0070248; PCT Application Publication Nos. WO 09/117531, WO 2005/081711, WO 04/010957: W002/088172 and WOO 1/24763, and U.S. Patent Nos.
  • Exemplary tubulysin compounds include compounds described in U.S. Patent Nos. 7,816,377; 7,776,814; 7,754,885; U.S. Publication Nos. 2011/0021568; 2010/004784; 2010/0048490; 2010/00240701 ; 2008/0176958; and PCT Application Nos.
  • WO 98/13375 WO 2004/005269; WO 2008/138561; WO 2009/002993; WO 2009/055562; WO 2009/012958; WO 2009/026177; WO 2009/134279; WO 2010/033733; WO 2010/034724; WO 2011/017249; WO 2011/057805; the disclosures of which are incorporated by reference herein in their entirety.
  • Exemplary vinca alkaloids include vincristine, vinblastine, vindesine, and navelbine (vinorelbine).
  • Suitable Vinca alkaloids that can be used in the present disclosure are also disclosed in U.S. Publication Nos. 2002/0103136 and 2010/0305149, and in U.S. Patent No. 7,303,749 Bl, the disclosures of which are incorporated herein by reference in their entirety.
  • Exemplary epothilone compounds include epothilone A, B, C, D, E and F, and derivatives thereof. Suitable epothilone compounds aud derivatives thereof are described, for example, in U.S. Patent Nos.
  • Exemplary cryptophycin compounds are described in U.S. Patent Nos. 6,680,311 and 6, 747,021, the disclosures of which are incorporated herein by reference in their entirety.
  • Exemplary ' platinum compounds include cisplatin (PLATINOL®), carboplatin (PARAPLATIN®), oxaliplatin (ELOX AT ⁇ NE®), iproplatin, ormaplatin, and tetraplatin.
  • Exemplary topoisomerase I inhibitors include camptothecin, camptothecin, derivatives, camptothecin analogs and non-natural camptothecins, such as, for example, CPT-11 (irinotecan), SN-38, topotecan, 9-aminocam ptothecin, rubitecan, gimateean, karenitecin, silatecan, lurtotecan, exatecan, diflomotecan, belotecan, lurtotecan and S39625.
  • Other camptothecin compounds that can be used in the present disclosure include those described in, for example, J. Med. Chem., 29:2358-2363 (1986); J. Med. Chem., 23:554 (1980): J. Med. Chem., 30: 1774 (1987).
  • Exemplary topoisomerase P inhibitors include azonafide and etoposide.
  • Additional agents acting on DNA include Lurbinectedin (PM01183), Trabectedin (also known as ecteinascidin 743 or ET-743) and analogs as described in WO 200107711, WO 2003014127.
  • Angiogenesis inhibitors include, but are not limited to, MetAP2 inhibitors.
  • Exemplary MetAP2 inhibitors include fumagillol analogs, meaning any compound that includes the fimiagillin core structure, including fumagillamine, that inhibits the ability of MetAP-2 to remove NHb-terminal methionines from proteins as described in Rodeschini et al., /. Org. Chem., 69, 357-373, 2004 and Liu, et al., Science 282, 1324-1327, 1998.
  • Non limiting examples of "fumagillol analogs” are disclosed in /. Org. Chem., 69, 357, 2004; J.Org, Chem., 70, 6870, 2005; European Patent Application 0 354787; /. Med. Chem., 49, 5645, 2006; Bioorg. Med. Chem.,
  • Exemplary cell cycle progression inhibitors include CDK inhibitors such as BMS-387032 and PD0332991; Rho-kinase inhibitors such as GSK429286; checkpoint kinase inhibitors such as AZD7762; aurora kinase inhibitors such as AZD1152, MLN8054 and MLN8237; PLK inhibitors such as BI 2536, BI6727 (Volasertih), GSK461364, ON-01910 (Estybon); and KSP inhibitors such as SB 743921, SB 715992 (ispmesib), MK-0731, AZD8477, AZ3146 and ARRY-520.
  • CDK inhibitors such as BMS-387032 and PD0332991
  • Rho-kinase inhibitors such as GSK429286
  • checkpoint kinase inhibitors such as AZD7762
  • aurora kinase inhibitors such as AZD1152, MLN8054
  • Exemplary PI3K/m-TOR/AKT signaling pathway inhibitors include phosphoinositide 3 -kinase (PI3K) inhibitors, GSK-3 inhibitors, ATM inhibitors, DNA-PK inhibitors and PDK-1 inhibitors.
  • PI3K phosphoinositide 3 -kinase
  • GSK-3 inhibitors GSK-3 inhibitors
  • ATM inhibitors DNA-PK inhibitors
  • PDK-1 inhibitors phosphoinositide 3 -kinase inhibitors
  • Exemplary ' PI3 kinase inhibitors are disclosed in U.S. Patent No.
  • 6,608,053 and include BEZ235, BGT226, BKM120, CAL101 CAL263, demethoxyviri din, GDC-0941, GSK615, IC87114, LY294002, Palomid 529, perifosine, PF-04691502, PX-866, SAR245408, SAR245409, SF1126, Wortmannin, XL147, XL765, GSK2126458 (Omipalisib), GDC-0326, GDC-0032 (T aseii sib.
  • RG7604 PF-05212384 (Gedatolisib, PKI-587), BAY 80-6946 (copanlisib), PF- 04691502, PF-04989216, PF-04979064, PI-103, PKI-402 VS-5584 (SB2343), GDC- 0941, NVP-BEZ235 (Dactoslisib), BGT226, NVP-BKM120 (Buparlisib), NVP- BYL719 (alpelisib), GSK2636771, AMG-319, GSK2269557, PQR309, PQR514, PQR530, PWT143, TGR-1202 (RP5264), PX-866, GDC-0980 (apitolisib), AZD8835, MEN 1117, D8-7423, ZSTK474, Cl DC-907.
  • IPI-145 IPI-145 (INK-1197, Duvelisib), AZD8186, XL 147 (SAR245408), XL765 (SAR245409), CAL-101 (Idelalisib, GS- 1101), GS-9820 (Acalisib) and KA2237.
  • Exemplary AKT inhibitors include, but are not limited to, AT7867, MK- 2206, Perifosine, GSK690693, Ipatasertib, AZD5363, TICIO, Afuresertib, SC79, AT13148, PUT-427. A-674563, and CCT128930.
  • Exemplary MAPK signaling pathway inhibitors include MEK, Ras, INK, B-Raf and p38 MAPK inhibitors.
  • Exemplary MEK inhibitors are disclosed in U.S. Patent No. 7,517,994 and include GDC-0973, GSK1120212, MSC1936369B, AS703026, R05126766 and R04987655, PD0325901, AZD6244, AZD 8330 and GDC-0973.
  • Exemplary ' B-raf inhibitors include CDC-0879, PLX-4032, and SB590885.
  • Exemplary B p38 MAPK inhibitors include BIRB 796, LY2228820 and SB202190.
  • RTK Receptor tyrosine kinases
  • Exemplary ’ inhibitors of ErbB2 receptor include but not limited to AEE788 (NVP-AEE 788), BIBW2992 (Afatinib), Lapatinib, Erlotinib (Tarceva), and Gefitinib (Iressa).
  • Exemplary ' RTK inhibitors targeting more then one signaling pathway include AP24534 (Ponatinib) that targets FGFR, FLT-3, VEGFR-PDGFR and Bcr-Abl receptors; ABT-869 (Linifanib) that targets FLT-3 and VEGFR- PDGFR receptors; AZD2171 that targets VEGFR-PDGFR, Flt- 1 and VEGF receptors; CHR-258 (Dovitinib) that targets VEGFR-PDGFR, FGFR, Flt- 3, and c-Kit receptors.
  • AP24534 Panatinib
  • ABT-869 Liifanib
  • AZD2171 that targets VEGFR-PDGFR, Flt- 1 and VEGF receptors
  • CHR-258 Dovitinib
  • Exemplary kinase inhibitors include inhibitors of the kinases ATM, ATR, CFIKl, CHK2, WEE1, and RSK.
  • the active agents are ATR inhibitors, such as but not limited to berzosertib (VX-970, M6620, or VE-822), AZD6738, or BAY1895344.
  • Exemplary protein chaperon inhibitors include HSP90 inhibitors.
  • Exemplary HSP90 inhibitors include 17AAG derivatives, BIIB021, B IIB028, 8NX- 5422, NVP-AUY-922, and KW-2478.
  • Exemplary HD AC inhibitors include Belinostat (PXD101), CUDC-101 ,
  • Doxinostat ITF2357 (Givinostat, Gavinostat), JNJ-26481585, LAQ824 (NVP- LAQ824, Dacinostat), LBH-589 (Panobinostat), MCI 568, MGCD0103 (Mocetinostat), MS-275 (Entmostat), PCI-24781, Pyroxamide (NSC 696085), SB939, Trichostatin A, and Vorinostat (SAHA).
  • Exemplary PARP inhibitors include iniparib (BSI 201), olaparib (AZD- 2281), ABT-888 (Veliparib), AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT-673, 3- aminobenzamide, A-966492, and AZD2461.
  • Exemplary ' Wnt/Hedgehog signaling pathway inhibitors include vismodegib (RG3616/GDC-0449), cyclopamine (11-deoxojervine) (Hedgehog pathway inhibitors), and XAV-939 (Wnt pathway inhibitor).
  • Exemplary RNA polymerase inhibitors include amatoxins.
  • Exemplary amatoxins include a- amanitins, b- amanitins, g- amanitins, e-amanitins, amanullin, amanullic acid, amaninamide, amanin, and proamanullin.
  • Exemplary proteasome inhibitors include bortezomib, carfilzomib, ONX 0912, CEP-18770, and MLN9708.
  • the drug of the disclosure is a non-natural camptothecin compound, vinca alkaloid, kinase inhibitor (e.g., P13 kinase inhibitor (GDC-0941 and PI- 103)), MEK inhibitor, KSP inhibitor, RNA polymerse inhibitor, PARP inhibitor, docetaxel, paditaxel, doxorubicin, duocarmycin, tubulysin, auristatin or a platinum compound.
  • kinase inhibitor e.g., P13 kinase inhibitor (GDC-0941 and PI- 103)
  • MEK inhibitor e.g., P13 kinase inhibitor (GDC-0941 and PI- 103)
  • KSP inhibitor e.g., kinase inhibitor (GDC-0941 and PI- 103)
  • MEK inhibitor e.g., P13 kinase inhibitor (GDC-0941 and PI- 103)
  • KSP inhibitor e.g., kina
  • the drug is a derivative of SN-38, vindesine, vinblastine, PI- 103, AZD 8330, auristatm E, auristatm F, a duocarmycin compound, tubulysin compound, or ARRY-520.
  • the drug used in the disclosure is a combination of two or more drugs, such as, for example, PI3 kinases and MEK inhibitors; broad spectrum cytotoxic compounds and platinum compounds; PARP inhibitors and platinum compounds; broad spectrum cytotoxic compounds and PARP inhibitors.
  • the active agent can be a cancer therapeutic.
  • the cancer therapeutics may include death receptor agonists such as the TNF-related apoptosis-inducing ligand (TRAIL) or Fas ligand or any ligand or antibody that binds or activates a death receptor or otherwise induces apoptosis.
  • TRAIL TNF-related apoptosis-inducing ligand
  • Fas ligand any ligand or antibody that binds or activates a death receptor or otherwise induces apoptosis.
  • Suitable death receptors include, but are not limited to, TNFR1, Fas, DR3, DR4, DR5, DR6, LTfiR and combinations thereof.
  • the active agent can he a DNA minor groove hinders such as lurbectidin and trabectidin.
  • the active agent can be E3 ubiquitin ligase inhibitors, adeubiquitinase inhibitors or an NFkB pathway inhibitor.
  • the active agent can be a phopsphatase inhibitors including inhibitors of FTP IB, SHP2, LYP, FAP-1, CD45, STEP, MKP-1, PRL, LMWPTP or CDC25.
  • the active agent can be an inhibitor of tumor metabolism, such as an inhibitor of GAPDH, GLUT1, HK II, PFK, GAPDH, PK, LDH orMCTs.
  • Tire active agent can target epigenetic targets including EZH2, MIX, DQTI-Iike protein (DOTH,), bromodomain-contaimng protein 4 (BRD4), BRD2, BRD3, NUT, ATAD2, or 8MYD2.
  • EZH2, MIX DQTI-Iike protein
  • DQTI-Iike protein DQTI-Iike protein
  • BRD4 bromodomain-contaimng protein 4
  • BRD2, BRD3, NUT ATAD2, or 8MYD2.
  • the active agent can target the body's immune system to help fight cancer, including moecules targeting IDOl, ID02, TDQ, CD39, CD73, A2A antagonists, STING activators, TLR agonists (TLR 1-13), ALK5, CBP/EP300 bromodomain, ARG1, ARG2, iNOS, PDE5, P2X7, P2Y11, COX2, EP2 Receptor, orEP4 receptor.
  • the active agent can target Bel-2, lAP, or fatty acid synthase.
  • the active agent can be 20-epi-l,25 dihydroxyvitamin D3, 4-ipomeanol, 5-ethynyluracil, 9-dihydrotaxol, abiraterone, acivicin, adambicin, acodazole hydrochloride, aeronine, acylfulvene, adecypenol, adozelesin, aldesleukin, all-tk antagonists, altretamine, ambamustine, ambomycm, ametantrone acetate, amidox, amifostine, aminoglutethimide, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, anthramycin, anti-dorsalizing morphogenetic protein- 1, antiestrogen, antineoplaston, antis
  • merbarone mercaptopurine, meterelin, methioninase, methotrexate, methotrexate sodium, metoclopramide, metoprine, meturedepa, microalgal protein kinase C inhibitors, MIF inhibitor, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitmdomide, mitocarcin, mitocromin, mitogilhn, mitoguazone, mitolactol, mitomalein, mitomycin, mitomycin analogs, mitonafide, mitosper, mitotane, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mitoxantrone hydrochloride, mofarotene, molgramostim, monoclonal antibody, human chorionic gonadotrophin, monophosphoryl lipid a/myobacterium cell wall SK, mopidamol, multiple drug
  • the active agent can he an inorganic or organometallic compound containing one or more metal centers.
  • the compound contains one metal center.
  • the active agent can be, for example, a platinum compound, a ruthenium compound (e.g., trans-[RuCl 2 (DMSO) 4 ], or trans -[RuCl 4 (imidazole) 2 , etc.), cobalt compound, copper compound, or iron compounds.
  • the active agent is a small molecule.
  • the active agent is a small molecule cytotoxin.
  • the active agent is eabazitaxel, or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof.
  • the acti ve agent is mertansine (DM1) or DM4, or an analog, derivative, prodrag, or pharmaceutically acceptable salt thereof.
  • DM1 or DM4 inhibits the assembly of microtubules by binding to tubulin. Structure of DM1 is shown below:
  • the active agent Z is Monomethyl auristatin E (MMAE), or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof. Structure of MMAE is shown below:
  • the active agent Z is a sequence-selective DNA minor-groove binding crossimking agent.
  • Z may be pyrrolobe nzodiazepine (PBD), a PBD dimer, or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof. Structures of PBD and PBD dimer are shown below: dimer).
  • the active agent Z is a topoisomerase I inhibitor, such as camptotheein, irinotecan, SN-38, or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof. -Ethyl- 10-hy droxy-camptotkecin)
  • WO2015184246 the contents of each of which are incorporated herein by reference in their entirety, such as hendamu stine, VDA, doxorubicin, pemetrexed, vorinostat, ienalidomide, docetaxei, 17-AAG, 5-FU, abiraterone, crizotinib, KW-2189, BUMB2 DC1, CC-1065, adozelesin, or derivatives/analogs thereof, may be used as an active agent in conjugates of the present disclosure.
  • the active agent is a topoisomerase inhibitor.
  • the topoisomerase inhibitor is a topoisomerase I inhibitor, including but not limited to irinotecan, topotecan, camptotheein, diflomoteean and lamellarin D, and fragments/derivatives/analogs thereof.
  • the topoisomerase inhibitor is atopoisomera.se II inhibitor such as etoposide (VP-16), teniposide, doxorubicin, daunombicin, mitoxantrone, arnsacrine, ellipticines, aurintricarboxyhc acid, and HU-331, and fragments/derivatives/analogs thereof.
  • VP-16 etoposide
  • doxorubicin teniposide
  • doxorubicin doxorubicin
  • daunombicin doxorubicin
  • mitoxantrone arnsacrine
  • ellipticines aurintricarboxyhc acid
  • HU-331 fragments/derivatives/analogs thereof.
  • BET inhibitors reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins such as BRD2, BRD3, BRD4, and BRDT, thus preventing protem-protein interaction between BET proteins and acetylated histones and transcription factors.
  • BET inhibitors may be used as anti-inflammation agent and/or anti -cancer agents.
  • any BET inhibitor may be used as an active agent.
  • the BET inhibitor is a BRD4 inhibitor.
  • the BET inhibitor or the BRD4 inhibitor may be a small molecule.
  • Non-limiting examples include JQi, I-BET 151 (GSK1210151A), I-BET 762 (GSK525762), OTX-015, TEN-010, CPI-203, CPI- 0610, olinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1 or MS645.
  • the conjugates of the present disclosure comprise JQ1, or fragments/derivatives/analogs thereof.
  • Targeting ligands include any molecule that can bind one or more HSP90 proteins.
  • targeting ligands can be peptides, antibody mimetics, nucleic acids (e.g., aptamers), polypeptides (e.g., antibodies), glycoproteins, small molecules, carbohydrates, or lipids.
  • the targeting moiety, X can be any HSP90 binding moiety such as, but not limited to, natural compounds (e.g., geldanamycin and radicicol), and synthetic compounds such as geldanamycin analogue 17-AAG (i.e., 17- allylaminogeldanamycin), a purine-scaffold HSP90 inhibitor series including PU24FCI (He H., et al, J. Med. Chem. , vol.49:381 (2006), the contents of which are incorporated herein by reference in their entirety), BIIB021 (Lundgren K., et al, Mol.
  • the targeting moiety may be a peptide, such as a bicyciic peptide or a modified bicyciic peptide.
  • the targeting moiety is a peptide having a sequence of (X)lC(X)mC(X)nC(X)o as disclosed in EP2474613, the contents of which are incorporated herein by reference in their entirety, wherein C is cysteine, X represents a random amino acid, m and n are numbers between I and 20 defining the length of intervening polypeptide segments and 1 and o are numbers betw een 0 and 20 defining the length of the flanking polypeptide segments.
  • the targeting moiety comprises at least 2 polypeptides covalently linked to tris-(bromomethyl) benzene (TBMB) at two or more amino acid residues as disclosed in US8680022 and US8778844, the contents of each of which are incorporated herein by reference in their entirety.
  • TBMB tris-(bromomethyl) benzene
  • the HSP90 binding moiety may be heterocyclic derivatives containing three heteroatoms.
  • W02009134110 to MATULI8 et al. discloses 4,5- diaryl thiadiazoles winch demonstrate good HSP90 binding affinity. Even though they have rather modest cell growth inhibition, they may be used as HSP90 binding moiety in conjugates of the present disclosure.
  • Another class of aza-heterocyciic adducts, namely triazole derivatives or their analogs, may be used as HSP90 binding moiety in conjugates of the present disclosure.
  • the 1,2,4-tri azole scaffold has been profusely documented as possessing HSP90 inhibiting properties.
  • WO2009139916 to BURLISON et al. discloses tricyclic 1,2,4-triazole derivatives inhibiting HSP90 at high micromolar concentrations. Any tricyclic 1,2,4- triazole derivatives disclosed in WO2009139916 or their derivatives/analogs may be used as HSP90 binding moiety in conjugates of the present disclosure.
  • Any trisubstituted 1 ,2,4- triazole derivatives disclosed in WO 2010017479 and WO 2010017545 (Synta Pharmaceuticals Corp.) or their derivatives/analogs, the contents of which are incorporated herein by reference in their entirety, may be used as HSP90 binding moiety in conjugates of the present disclosure.
  • a triazolone-containing HSP90 inhibitor named ganetespib previously referred as to 8TA-9090, or as its highly soluble phosphate prodrug STA- 1474) disclosed in W02006055760 (Synta Pharmaceuticals Corp.), the contents of which are incorporated herein by reference in their entirety, or its derivatives/analogs may be used as HSP90 binding moiety in conjugates of the present disclosure.
  • ganetespib or its derivatives/analogs may be used a targeting moiety.
  • ganetespib derivatives/analogs are shown below.
  • Onalespib (ATI 3387) or its derivatives/analogs may be used as a targeting moiety in the conjugates of the present disclosure.
  • Onalespib and non-limiting examples of Onalespib derivatives/analogs are shown below.
  • the HSP90 targeting moiety comprises r its fragments/derivatives/analogs; or r its fragments/derivatives/analogs.
  • HSP90 binding moiety in the conjugates of the present disclosure, such as:
  • R 1 may be alkyl, aryl, halide, carboxamide or sulfonamide
  • R2 may be alkyl, cycloalkyl, aryl or heteroaryl, wherein when R2 is a 6 membered aryl or heteroaryl, R2 is substituted at the 3- and 4- positions relative to the connection point on the triazole ring, through which a linker I. is attached
  • R3 may be SH, OH, -CONHR4, and or heteroaryl, wherein when R3 is a 6 membered aryl or heteroaryl, R3 is substituted at the 3 or 4 position;
  • R1 may be alkyl, and, halo, carboxamide, sulfonamido; and R2 may be optionally substituted alkyl, cycloalkyl, aryl or heteroaryl.
  • R2 may be optionally substituted alkyl, cycloalkyl, aryl or heteroaryl.
  • examples of such compounds include 5-(2,4-dihydroxy-5- isopropylphenyl) ⁇ N ⁇ (2-morpholmoethyl)-4-(4 ⁇ (morpholinomethyl)phenyl)-4H-l,2,4 ⁇ triazole-3-carboxamide and 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(4- methylpiperazin- 1 -yl)phenyl)-N-(2,2,2-trifluoroethyl)-4H- 1 ,2,4-triazole-3 - carboxamide;
  • Formula Ill wherein X, Y, and Z may independently be CH
  • R1 may be alkyl, aryl, halide, carboxamido or sulfonamido
  • R2 may be substituted alkyl, cycloalkyl, aryl or heteroaryl, where a linker L is connected directly or to the extended substitutions on these rings
  • R3 may be SH, OH, NR4R5 AND -CONHR6, to which an effector moiety may be connected
  • R4 and R5 may independently be H, alkyl, aryl, or heteroaryl
  • R6 may- be alkyl, aryl, or heteroaryl, having a minimum of one functional group to which an effector moiety may be connected; or
  • R1 may be alkyl, aryl, halo, carboxamido or sulfonamido
  • R2 and R3 are independently C1-C5 hydrocarbyl groups optionally substituted with one or more of hydroxy, halogen, C1 -C2 alkoxy, amino, mono- and di-C1-C2 alkylamino; 5- to 12- membered aryl or heteroaryl groups; or, R2 and R3, taken together with the nitrogen atom to which they are attached, form a 4- to 8- membered monocyclic heterocyclic group, of whi ch up to 5 ring members are selected from O, N and S. Examples of such compounds include AT-13387.
  • the HSP90 targeting moiety may be Ganetespib, Luminespib (AUY-922, N VP-AU Y 922), Debio-0932, MPC-3100, Onalespib (AT-13387), SNX-2112, 17- amino-geldanamycin hydroquinone, PU-H71, AT13387, or derivatives/analogs thereof.
  • the HSP90 targeting moiety may be SNX5422 (PF-04929113), or any other HSP90 inhibitors disclosed in US 8080556 (Pfizer), W02008096218 (Pfizer), W02006117669 (Pfizer), W02008059368 (Pfizer), W02008053319 (Pfizer), W02006117669 (Pfizer), EP1885701 (Novartis), EP1776110 (Novartis), EP2572709 (Novartis), WO2012131413 (Debiopharm), or WO2012131468 (Debiopharm), the contents of each of which are incorporated herein by reference in their entirety.
  • the HSP90 targeting moiety may also be PU-H71, an HSP90 inhibitor that is 124 I radiolabeled for PET imaging or its derivative s/analogs.
  • Conjugates comprising SNX-2112, 17-amino-geldanamycin hydroquinone, PU-H71, or AT13387 may have a structure of:
  • the HSP90 targeting moiety comprises a Sansalvamide A derivative.
  • Sansalvamide A (San A) is a cyclic pentapeptide isolated from amarine fungus and hinds to H8P90. Any Di-Sansalvamide A derivative (dimerized San A molecules) disclosed in Alexander et al., J Med Chem., vol.52(24):7927 (2009), the contents of which are incorporated herein by reference in their entirety, for example, the Di-San A molecules in Figure 1 of Alexander, may be used as a targeting moiety of the conjugate of the current disclosure.
  • the HSP90 targeting moiety comprises alkynyl pyrrolo[2.,3 ⁇ d]pyrimidines and related analogs such as HSP90 inhibitors disclosed in US7544672 (CONFORMA TH ERAPEUTICS), the contents of which are incorporated herein by reference in their entirety.
  • the HSP90 targeting moiety compriese any HSP90 inhibitor disclosed in WO201011742.5 (Biogen), the contents of which are incorporated herein by reference in their entirety.
  • Extracellular HSP90 eHSP90
  • HSP90 In normal cells, secretion of HSP90 occurs when cells are under environmental stress such as heat, drags, cytokines, UV, and/or gamma rays.
  • the main function of the extracellular FI8P90 (eHSP90) is to help tissue repair by promoting the cells at the edge of damaged tissue to migrate into the damaged area.
  • constitutively activated oncogenes trigger HSP90 secretion even without any environmental stress.
  • Secreted Hsp90 by tumors eHSP90a promotes both tumor and tumor stroma cell migration during invasion and metastasis.
  • HSP90a The extracellular promotility function of HSP90a depends on a 115-amino acid fragment (F-5) on the surface of HSP90 (Li et al., Int Rev Cell Mol Biol. , vol .303:203-235 (2013), the contents of which are incorporated herein by reference in their entirety).
  • F-5 115-amino acid fragment
  • eHSP90 has been shown to be presen t on the surface of tumor cells and to also be capable of being internalized (Crowe et al., ACS Chem. Biol. , vol.12: 1047-1055 (2017)).
  • the surface expression of eHSP90 m tumor cells thus represents a target tor directing therapies selectively to tumors over healthy cells. Therefore, eHSP9Q (eHSP90a in particular) may be a good target for treating tumors.
  • eHSP90 can be measured using the method known in the art, such as ELISA, RIA, EIA, sandwich assay, Western Blot analysis, immunostaining, flow' cytometry and immunohistological staining.
  • the targeting moiety selectively binds to eHSP90. In some embodiments, the targeting moiety binds to F-5 region of eHSP90.
  • the targeting moiety has low cell -permeability and prefers to bind to cell surface eHSP90. In some embodiments, the targeting moiety is cell-impermeable and binds exclusive to eHSP90. In some embodiments, the conjugates comprising the targeting moieties have a low cell permeability or is cell- impermeable.
  • HS- 131 (100) is a fluorescent specific small-molecule Hsp90 inhibitor. It is not cell permeable and it binds exclusively to eHsp90.
  • the five isogenic cell lines (67NR, 168FARN, 4 ⁇ 7, and 4T1) were isolated from a single spontaneous mammary tumor. They cells exhibit varying degrees of metastatic disease when injected into mice. 100 was internalized to a higher extent in 4T1 cells (the most aggressive of the five lines) over the less metastatic lines.
  • the targeting moieties comprise HS-23, HS-131, (disclosed in Crowe et ah, ACS Chem.
  • the targeting moiety comprises B IIB021, or any compound disclosed in WO2010117425, and fragments/analogs/derivatives thereof, such as the compounds of Formula I or Formula II or the compounds in Table 2 of WO2010117425, and the structures shown below:
  • the targeting moiety comprises an antibody or antibody fragment which binds to human extracellular Hsp90.
  • the targeting moiety may be a monoclonal antibody disclosed in US 7959915 (Tufts University), the contents of which are incorporated herein by reference in their entirety, such as mAh 1.5.1.
  • the targeting moiety maybe an anti- H8P90 monoclonal antibody disclosed in US20110280881 (Riken Corp.), the contents of which are incorporated herein by reference in their entirety, wherein the antibody binds to an epitope comprising an amino acid sequence selected from the amino acid sequence V X 1 X2EX3 PPLEGDX4 (wherein each of XI to X4, which may be identical to or different from each other, represents an arbitrary " amino acid) (SEQ ID NO: 1 in US20110280881 ) or the amino acid sequence HX5IX6ETLRQKAE (wherein each of X5 to X6, which may be identical to or different from each other, represents an arbitrary amino acid) (SEQ ID NO:2 in US20110280881), and wherein the antibody recognizes cell surface HSP90.
  • the antibody binds to an epitope comprising an amino acid sequence selected from the amino acid sequence V X 1 X2EX3 PPLEGDX4 (wherein each of XI
  • the targeting moiety or moieties of the conjugate are present at a predetermined molar weight percentage from about 0.1 % to about 10%, or about 1% to about 10%, or about 10% to about 20%, or about 20% to about 30%, or about 30% to about 40%, or about 40% to about 50%, or about 50% to about 60%, or about 60% to about 70%, or about 70% to about 80%, or about 80% to about 90%, or about 90% to about 99% such that the sum of the molar weight percentages of the components of the conjugate is 100%.
  • the amount of targeting moieties of the conjugate may also be expressed in terms of proportion to the active agent(s), for example, in a ratio of ligand to active agent of about 10: 1 , 9: 1, 8: 1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4; 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.
  • the conjugates contain one or more linkers attaching the active agents and targeting moieties.
  • the linker, Y is bound to one or more active agents and one or more targeting ligands to form a conjugate.
  • the linker Y is attached to the targeting moiety X and the active agent Z by functional groups independently selected from an ester bond, disulfide, amide, aeylhydrazone, ether, carbamate, carbonate, and urea.
  • the linker can be attached to either the targeting ligand or the active drug by a non-cleavable group such as provided by the conjugation between a thiol and a maleimide, an azide and an alkyne.
  • the linker is independently selected from the group consisting alkyl, cyeloalkyf, heterocyclyl, and, and heteroaryl, wherein each of the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups optionally is substituted with one or more groups, each independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, wherein each of the carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, where
  • the linker comprises a cleavable functionality that is eleavable.
  • the cleavable functionality may be hydrolyzed in vivo or may be designed to be hydrolyzed enzymatically, for example by Cathepsin B.
  • a “cleavable” linker refers to any linker which can be cleaved physically or chemically. Examples for physical cleavage may be cleavage by light, radioactive emission or heat, while examples for chemical cleavage include cleavage by re- dox-reactions, hydrolysis, pH-dependent cleavage or cleavage by enzymes.
  • the cleavable functionality may be a disulfide bond or a carbamate bond.
  • the linker may be selected from dicarboxylate derivatives of succinic acid, glutarie acid or diglycolic acid.
  • the linker Y may be X’“R'-Y"-R 2 -Z" and the conjugate can he a compound according to Formula Ia: wherein X is a targeting moiety defined above; Z is an active agent; X " . R 1 , Y’, R 2 and Z’ are as defined herein.
  • X’ is either absent or independently selected from carbonyl, amide, urea, amino, ester, aryl, arylearhonyl, aryloxy, arylamino, one or more natural or unnatural amino acids, thio or succmimido;
  • R 1 and R 2 are either absent or comprised of alkyl, substituted alkyl, asyl, substituted aryl, polyethylene glycol (2-30 units);
  • Y’ is absent, substituted or unsubstituted 1 ,2-di am inoe thane, polyethylene glycol (2-30 units) or an amide;
  • Z" is either absent or independently selected from carbonyl, amide, urea, amino, ester, aryl, arylcarbonyl, aryloxy, arylamino, thio or succinimido.
  • the linker can allow one active agent molecule to be linked to two or more ligands, or one ligand to be linked to two or more active agent molecule.
  • a in Formula la is a spacer unit, either absent or independently selected from the following substituents.
  • C in Formula Ic is a branched unit containing three to six functionalities for covalently attaching spacer units, ligands, or active drugs, selected from amines, carboxylic acids, thiols, or suceinimides, including amino acids such as lysine, 2,3- diaminopropanoic acid, 2,4-diaminobutyric acid, glutamic acid, aspartic acid, and cysteine.
  • the active agent Z is a BRD4 inhibitor, wherein the active agent Z and the targeting moiety X are connected with a linker.
  • the linkers are cleavable. in some embodiments, the linkers are non- cleavable.
  • the conjugates of the present disclosure comprise JQ1 or its fragments/derivatives/analogs as active agents.
  • Non-limiting examples include Compounds 1 - 27, structures shown in the table below: Table 1 : Non-Limiting Examples of Conjugates Comprising JO1 or its
  • the conjugates of the present disclosure may further comprise at least one external linker connected to a reacting group that reacts with a functional group on a protein or an engineered protein or derivatives/analogs/mimics thereof, or comprise at least one external linker connected to a pharmacokinetic modulating unit.
  • the external linkers connecting the conjugates and the reacting group or the pharmacokinetic modulating units may be cleavable linkers that allow release of the conjugates.
  • the conjugates may be separated from the protein or pharmacokinetic modulating units as needed.
  • the conjugates of the present disclosure may further comprise at least one permeability modulating unit, in some embodiments, the permeability modulating unit is attached to the payload of the conjugate, wherein the pemicabiity modulating unit regulates the cell membrane permeability of the payload. In some embodiments, the permeability modulating unit reduces the permeability of the payload. Not willing to be bound by any theory, once the payload is released from the conjugate, the permability modulating unit that is atached to the payload reduces the cell membrane permability of the payload, increases the retention time of the payload in target cells, improves the intracellular accumulation of the payload, and improves its efficacy.
  • the permeability modulation unit does not adversely impact the permeability of the conjugate or the binding capability of the targeting moiety.
  • the permeability modulation unit is active only after the payload is released from the conjugate, e.g., after the cleavable linker between the payload and the targeting moiety is cleaved.
  • the permeability modulating unit is a functional group that is covalently attached to the payload of the conjugate. In some embodiments, the permeability modulating unit is an integral part of the payload. [0124] In some embodiments, the permeability modulating unit is attached to the payload via an external linker. The external linker may be a non-cleavable linker. [0125] The passive permeation of a payload through the biological cell membranes is strongly dependent on the molecule physicochemical properties.
  • the permeability moduclating unit is hydrophilic. In some embodiments, the permeability moduclating unit is hydrophobic. In some embodiments, the permeability moduciating unit is polar. In some embodiments, the permeability moduclating unit is charged at physiological pH. For example, the permeability modulating unit may be positively charged, negati vely charged, or a combination of multiple charges.
  • Non-limiting examples of the permabihty modulating unit include a functional group that has at least one nitrogen, such as a piperazine functional group.
  • compositions are administered to humans, human patients or subjects.
  • active ingredient generally refers to the conjugate to be delivered as described herein.
  • compositions which arc suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation.
  • Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and/or turkeys.
  • Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology, in general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • a pharmaceutical composition in accordance with the disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amo unt of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • compositions in accordance with the disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100%, e.g., between .5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient.
  • the conjugates of the present disclosure can be formulated using one or more excipients to: (l) increase stability; (2) pennit the sustained or delayed release (e.g., from a depot formulation of the monomaleimide); (3) alter the biodistribution (e.g., target the monomaleimide compounds to specific tissues or cell types); (4) alter the release profile of the monomaleimide compounds in vivo.
  • excipients include any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, and preservatives.
  • Excipients of the present disclosure may also include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, hyaluronidase, nanoparticle mimics and combinations thereof. Accordingly, the formulations of the disclosure may include one or more excipients, each in an amount that together increases the stability of the monomaleimide compounds.
  • compositions may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable excipient includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington s The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippineott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety) discloses various excip
  • a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure, in some embodiments, an excipient is approved for use in humans and for veterinary use. in some embodiments, an excipient is approved by United States Food and Drug Administration. In some embodiments, an excipient is pharmaceutical grade. In some embodiments, an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia.
  • USP United States Pharmacopoeia
  • EP European Pharmacopoeia
  • British Pharmacopoeia the British Pharmacopoeia
  • International Pharmacopoeia International Pharmacopoeia
  • compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical compositions.
  • Exemplary ' diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystallme cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof.
  • Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycol ate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross- linked poly(vmyl-pyrrofidone) (crospovidone), sodium carboxymethyl starch (sodium starch giycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM®), sodium lauryl sulfate, quaternary ammonium compounds, etc., and/or combinations thereof.
  • crospovidone cross- linked poly(vmyl-pyrrofi
  • Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and VEEGUM® [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • polyoxyethylene monostearate [MYRJ®45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and SOLUTOL®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. CREMOPHOR®), polyoxyethylene ethers, (e.g.
  • polyoxyethylene lauryl ether [BRTJ®30]), polyvinyl-pyrro lidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PLUORINC®F 68, POLOXAMER®188, cetrimonium bromide, cetylpyridin ium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol,); natural and synthetic gums (e.g.
  • acacia sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylceliulose, methylcellulose, etliylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohol; etc.; and combinations thereof.
  • Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives.
  • Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl pahnitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl galiate, sodium ascorbate, sodium bisulfite, sodium metabi sulfite, and/or sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or tri sodium edetate.
  • EDTA ethylenediaminetetraacetic acid
  • citric acid monohydrate disodium edetate
  • dipotassium edetate dipotassium edetate
  • edetic acid fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or tri sodium edetate.
  • antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chloroeresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phen ylmercuric nitrate, propylene glycol, and/or thimerosal.
  • Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, bydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid.
  • Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol.
  • Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid.
  • preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT PLUS ⁇ , PHENONIP®, methylparahen, GERMALL®115, GERMABEN®ll, NEOLONETM, KATHONTM, and/or EUXYL®.
  • Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levuiinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water
  • Exemplary' lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
  • Exemplary' oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquan
  • oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof.
  • Excipients such as cocoa butter and suppository' waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents can be present in the composition, according to the judgment of the formulator.
  • the conjugates the present disclosure may be administered by any route which results in a therapeutically effective outcome. These include, but are not limited to enteral, gastroenteral, epidural, oral, transdermal, epidural (peridural), intracerebral (into the cerebrum), intracerebrove ntricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal, (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal, (infusion or injection into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavemous injection, ( into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration,
  • the formulations described herein contain an effective amount of conjugates in a pharmaceutical carrier appropriate for administration to an individual in need thereof.
  • the formulations may be administered parenterally (e.g., by injection or infusion).
  • the formulations or variations thereof may be administered in any manner including enterally, topically (e.g., to the eye), or via pulmonary administration. In some embodiments the formulations are administered topically.
  • the conjugates can be formulated for parenteral delivery, such as injection or infusion, in the form of a solution, suspension or emulsion.
  • the formulation can be administered systemically, regionally or directly to the organ or tissue to be treated.
  • Parenteral formulations can be prepared as aqueous compositions using techniques is known in the art. Typically, such compositions can be prepared as injectable formulations, for example, solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution medium prior to injection; emulsions, such as water-iu-oil (w/o) emulsions, oil-in- water (o/w) emulsions, and microemulsions thereof, liposomes, or emulsomes.
  • injectable formulations for example, solutions or suspensions
  • solid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution medium prior to injection emulsions, such as water-iu-oil (w/o) emulsions, oil-in- water (o/w) emulsions, and microemulsions thereof, liposomes, or emulsomes.
  • emulsions such as water-iu-oil (w/o)
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, com oil, sesame oil, etc.), and combinations thereof.
  • polyols e.g., glycerol, propylene glycol, and liquid polyethylene glycol
  • oils such as vegetable oils (e.g., peanut oil, com oil, sesame oil, etc.)
  • an isotonic agent is included, for example, one or more sugars, sodium chloride, or other suitable agent known in the art.
  • Solutions and dispersions of the conjugates cau be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, surfactants, dispersants, emulsifiers, pH modifying agents, and combinations thereof,
  • Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface active agents.
  • Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosiiCcinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimeth ylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl -4- oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG -400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG- 1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolaraide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N- dodecyl- ⁇ -akmine, sodium N-lauryl- ⁇ -iminodipropionate, myristoamphoacetate, iauryl betaine and lauryl sulfo betaine.
  • the formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.
  • the formulation may also contain an antioxidant to prevent degradation of the active agent(s).
  • the formulation is typically buffered to a pH of 3-8 for parenteral administration upon reconstitution.
  • Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers, if using 10% sucrose or 5% dextrose, a buffer may not be required.
  • Water soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.
  • Sterile injectable solutions can be prepared by incorporating the conjugates in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized conjugates into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above, in the case of sterile powders for the preparation of sterile injectable solutions, examples of methods of preparation include vacuum-drying and freeze-drying techniques that yield a powder of the particle plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are known in the art.
  • compositions for parenteral administration can be in the form of a sterile aqueous solution or suspension of conjugates formed from one or more polymer-drug conjugates.
  • Acceptable solvents include, for example, water. Ringer's solution, phosphate buffered saline (PBS), and isotonic sodium chloride solution.
  • PBS phosphate buffered saline
  • the formulation may also he a sterile solution, suspension, or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as 1,3-butanediol.
  • the formulation is distributed or packaged in a liquid form.
  • formulations for parenteral administration can be packed as a solid, obtained, for example by lyophilization of a suitable liquid formulation.
  • the solid can be reconstituted with an appropriate carrier or diluent prior to administration.
  • Solutions, suspensions, or emulsions for parenteral administration may be buffered with an effective amount of buffer necessary to maintain a pH suitable for ocular administration.
  • Suitable buffers are well known by those skilled in the art and some examples of useful buffers are acetate, borate, carbonate, citrate, and phosphate buffers.
  • Solutions, suspensions, or emulsions for parenteral administration may also contain one or more tonicity agents to adjust, the isotonic range of the formulation. Suitable tonicity agents are well known in the art and some examples include glycerin, sucrose, dextrose, mannitol, sorbitol, sodium chloride, and other electrolytes. [0160] Solutions, suspensions, or emulsions for parenteral administration may also contain one or more preservatives to prevent bacterial contamination of the ophthalmic preparations.
  • Suitable preservatives include polyhexamethylenebiguanidine (PHMB), benzalkonium chloride (BAK), stabilized oxyehloro complexes (otherwise known as Purite®), phenylmercuric acetate, chlorobutanol, sorbic acid, chlorhexidine, benzyl alcohol, parabens, thimerosal, and mixtures thereof.
  • PHMB polyhexamethylenebiguanidine
  • BAK benzalkonium chloride
  • Purite® stabilized oxyehloro complexes
  • phenylmercuric acetate chlorobutanol
  • sorbic acid chlorhexidine
  • chlorhexidine benzyl alcohol
  • parabens parabens
  • thimerosal and mixtures thereof.
  • Solutions, suspensions, or emulsions for parenteral administration may also contain one or more excipients known art, such as dispersing agents, wetting agents, and suspending agents.
  • the conjugates can be formulated for topical adm inistration to a mucosal surface
  • Suitable dosage forms for topical administration include creams, ointments, salves, sprays, gels, lotions, emulsions, liquids, and transdermal patches.
  • the formulation may be formulated for transmucosal transepithelial, or transendothelial administration.
  • the compositions contain one or more chemical penetration enhancers, membrane permeability agents, membrane transport agents, emollients, surfactants, stabilizers, and combination thereof.
  • the conjugates can be administered as a liquid formulation, such as a solution or suspension, a semi-solid formulation, such as a lotion or ointment, or a solid formulation.
  • the conjugates are formulated as liquids, including solutions and suspensions, such as eye drops or as a semi-solid formulation, to the mucosa, such as the eye or vaginally or rectally.
  • Suitable non-ionic surfactants include emulsifying wax, glyceryl rnonooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyciodextrins, glycerin monostearate, poloxamer, povidone and combinations thereof
  • the non-ionic surfactant is stearyl alcohol.
  • Emmulsifiers are surface active substances which promote the suspension of one liquid in another and promote the formation of a stable mixture, or emulsion, of oil and water. Common emulsifiers are: metallic soaps, certain animal and vegetable oils, and various polar compounds.
  • Suitable emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chain triglycerides, methylcellulose, mineral oil and lanolin alcohols, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, self-emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium iauryl sul
  • Suitable classes of penetration enhancers include, but are not limited to, fatty alcohols, faty acid esters, fatty acids, fatty alcohol ethers, amino acids, phospholipids, lecithins, cholate salts, enzymes, amines and amides, complexing agents (liposomes, cyciodextrins, modified celluloses, and diimides), macrocyclics, such as macrocylic lactones, ketones, and anhydrides and cyclic ureas, surfactants, N-m ethyl pyrrolidones and derivatives thereof, DMSO and related compounds, ionic compounds, azone and related compounds, and solvents, such as alcohols, ketones, amides, polyols (e.g., glycols). Examples of these classes are known in the art.
  • the present disclosure provides methods comprising administering conjugates containing the conjugate as described herein to a subject in need thereof.
  • Conjugates containing the conjugates as described herein may be administered to a sub j ect using any amount and any route of administration effective for preventing or treating or imaging a disease, disorder, and/or condition (e.g., a disease, disorder, and/or condition relating to working memory deficits).
  • a disease, disorder, and/or condition e.g., a disease, disorder, and/or condition relating to working memory deficits.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like.
  • compositions in accordance with the disclosure are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure may he decided by the attending physician within the scope of sound medical judgment.
  • Tire specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed: the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical aits,
  • compositions in accordance with the present disclosure may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg / kg, or from about 1 mg/kg to about 25 mg/kg, from about 25 mg / kg to about 50 mg / kg, from about 50 mg/kg to about 100 mg/kg, from about 100 mg/leg to about 125 mg/kg, from about 125 mg/kg to about 150 mg/kg, from about 150 mg/ to about 1
  • the desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage may he delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • multiple administrations e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations.
  • split dosing regimens such as those described herein may be used.
  • the concentration of the conjugates of the present disclosure may be between about 0.01 mg/mL to about 50 mg/mL, about 0.1 mg/rnL to about 25 mg/m L, about 0.5 mg/mL to about 10 mg/mL, or about 1 mg/mL to about 5 mg/mL in the pharmaceutical composition .
  • a “split dose ” is the division of single unit dose or total daily dose into two or more doses, e.g, two or more administrations of the single unit dose.
  • a “single unit dose” is a dose of any therapeutic administed in one dose/at one time/single route/single point of contact, i.e., single administration event.
  • a “total daily dose” is an amount given or prescribed in 24 hr period, it may be administered as a single unit dose.
  • the monomaleimide compounds of the present disclosure are administed to a subject in split doses. Tire monomaleimide compounds may be formulated in buffer only or in a formulation described herein.
  • a pharmaceutical composition described herein can be formulated into a dosage torn described herein, such as a topical, intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, and subcutaneous).
  • injectable e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, and subcutaneous.
  • Liquid dosage forms for parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs.
  • liquid dosage fonns may comprise inert diluents commonly used in the art including, but not limited to, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dirnethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art
  • compositions may be mixed with solubilizing agents such as CREMOPHOR®, alcohols, oils, modified oils, glycols, polysorbat.es, eyelodextrins, polymers, and/or combinations thereof.
  • solubilizing agents such as CREMOPHOR®, alcohols, oils, modified oils, glycols, polysorbat.es, eyelodextrins, polymers, and/or combinations thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art and may include suitable dispersing agents, wetting agents, and/or suspending agents.
  • Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenteraliy acceptable diluents and/or solvents, for example, a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer's solution, U.S.P., and isotonic sodium chloride solution.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid am be used in the preparation of injectable s.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of monomaleimide compound release can he controlled.
  • biodegradable polymers include, but are not limited to, poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations may be prepared by entrapping the monomaleimide compounds in liposomes or microemulsions which are compatible with body tissues.
  • Formulations described herein as being useful for pulmonary' delivery' may also be used for intranasal delivery of a pharmaceutical composition.
  • Another formulation suitable for intranasal administration may be a coarse powder comprising the active ingredient and having an average particle from about 0.2 ⁇ m to 500 ⁇ m.
  • Such a formulation may be administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose,
  • Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, contain about 0.1% to 20% (w/w) active ingredient, where the balance may comprise an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 am to about 200 mn, and may further comprise one or more of any additional ingredients described herein.
  • Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • conjugates or formulations as described herein can be administered to treat any hyperproliferative disease, metabolic disease, infectious disease, or cancer, as appropriate.
  • Formulations may be administered by injection, orally, or topically, typically to a mucosal surface (lung, nasal, oral, buccal, sublingual, vaginally, rectally) or to the eye (intraocularly ortransocularly).
  • cancer embraces any disease or malady characterized by uncontrolled cell proliferation, e.g., hyperproliferation. Cancers may be characterized by tumors, e.g., solid tumors or any neoplasm.
  • the cancer is a solid tumor.
  • Large drag molecules have limited penetration in solid tumors. The penetration of large drug molecules is slow.
  • small molecules such as conjugates of the present disclosure may penetrate solid tumors rapidly and more deeply. Regarding penetration depth of the drugs, larger molecules penetrate less, despite having snore durable pharmacokinetics. Small molecules such as conjugates of the present disclosure penetrate deeper.
  • Dreher et al. (Dreher et al, JNCI, vol.98(5):335 (2006), the contents of which are incorporated herein by reference in their entirety) studied penetration of dextrans with different sizes into a tumor xenograft. As summarized in Fig.
  • conjugates of the present disclosure reach at least about 25 ⁇ m, about 30 ⁇ m, about 35 ⁇ m, about 40 ⁇ m, about 45 ⁇ m, about 50 ⁇ m, about 75 ⁇ m, about 100 ⁇ m, about 150 ⁇ m, about 200 ⁇ m, about 250 ⁇ m, about 300 ⁇ m, about 400 ⁇ m, about 500 ⁇ m, about 600 ⁇ m, about 700 ⁇ m, about 800 ⁇ m, about 900 ⁇ m, about 1000 ⁇ m, about 1100 ⁇ m, about 1200 ⁇ m, about 1300 ⁇ m, about 1400 ⁇ m or about 1500 ⁇ m into the solid tumor from the vascular surface of the tumor.
  • Zero distance is defined as the vascular surface of the tumor, and every distance greater than zero is defined as the distance measured in three dimensions to the nearest vascular surface.
  • conjugates of the present disclosure penetrate to the core of the tumor.
  • ‘"Core” of the tumor refers to the central area of the tumor.
  • the distance from any part of the core area of the tumor to the vascular surface of the tumor is between about 30% to about 50% of the length or width of the tumor.
  • the distance from any part of the core area of the tumor to the center point of the tumor is less than about 20% of the length or width of the tumor.
  • the core area of the tumor is roughly the center 1/3 of the tumor.
  • conjugates of the present disclosure penetrate to the middle of the solid tumor.
  • “Middle” of the tumor refers to the middle area of the tumor.
  • the distance from any part of the middle area of the tumor to the vascular surface of the tumor is between about 15% and about 30% of the length or the width of the tumor.
  • the distance from any part of the middle area of the tumor to the center point of the tumor is between about 20% to about 35% of the length or width of the tumor.
  • the middle area of the tumor is roughly between the center 1/3 of the tumor and the outer 1/3 of the tumor.
  • the subject may be otherwise free of indications for treatment with the conjugates or formulations.
  • methods include use of cancer cells, including but not limited to mammalian cancer cells. In some instances, the mammalian cancer cells are human cancer cells.
  • the conjugates or formulations of the present teachings have been found to inhibit cancer and/or tumor growth. They may also reduce, including cell proliferation, invasiveness, and/or metastasis, thereby rendering them useful for the treatment of a cancer.
  • the conjugates or formulations of the present teachings may be used to prevent the growth of a tumor or cancer, and/or to prevent the metastasis of a tumor or cancer.
  • compositions of the present teachings may be used to shrink or destroy a cancer.
  • the conjugates or formulations provided herein are useful for inhibiting proliferation of a cancer cell.
  • the conjugates or formulations provided herein are useful for inhibiting cellular proliferation, e.g., inhibiting the rate of cellular proliferation, preventing cellular proliferation, and/or inducing cell death, in general, the conjugates or formulations as described herein can inhibit cellular proliferation of a cancer cell or both inhibiting proliferation and/or inducing cell death of a cancer cell.
  • cell proliferation is reduced by at least about 25%, about 50%, about 75%, or about 90% after treatment with conjugates or formulations of the present disclosure compared with cells with no treatment.
  • cell cycle arrest marker phospho histone H3 (PH3 or PHH3) is increased by at least about 50%, about 75%, about 100%, about 200%, about 400% or about 600% after treatment with conjugates or formulations of the present disclosure compared with cells with no treatment.
  • cell apoptosis marker cleaved caspase-3 (CCS) is increased by at least 50%, about 75%, about 100%, about 200%, about 400% or about 600% after treatment with conjugates or formulations of the present disclosure compared with cells with no treatment.
  • conjugates or particles of the present disclosure are effective for inhibiting tumor growth, whether measured as a net value of size (weight, surface area or volume) or as a rate over time, in multiple types of tumors.
  • size of a tumor is reduced by about 60 % or more after treatment with conjugates or formulations of the present disclosure.
  • the size of a tumor is reduced by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, by a measure of weight, and/or area and/or volume,
  • the cancers treatable by methods of the present teachings generally occur in mammals.
  • Mammals include, for example, hitmans, non-human primates, dogs, cats, rats, mice, rabbits, ferrets, guinea pigs horses, pigs, sheep, goats, and cattle, in various embodiments, Cancers include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytie), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myo
  • cancers include primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gall bladder cancer, bile duet cancer, small intestine cancer, urinary tract cancer, kidney cancer, uroth elium cancer, female genital tract cancer, uterine cancer, gestational trophoblastic disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary gland cancer, hemangioma, sarcoma arising from bone and soft tissues, Kaposi’s sarcoma, nerve cancer, ocular cancer, meningial cancer, glioblastomas, neuromas, neuroblastomas, Schwannomas, solid tumors arising from hematopoietic malignancies such as leukemias, metastatic melanoma, recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, primary peritone
  • the conjugates or formulations as described herein are used to treat small cell lung cancer. About 12%-15% of patients having lung cancer have small cell lung cancer. Survival in metastatic small cell lung cancer is poor. Survival rate is below 5% five years after diagnosis. US incidence of small cell lung cancer is about 26K-30K. [0194] In some embodiments, the conjugates or formulations as described herein are used to treat patients with tumors that express or over-express the H8P90.
  • a feature of conjugates or formulations of the present disclosure is relatively low toxicity to an organism while maintaining efficacy at inhibiting, e.g. slowing or stopping tumor growth.
  • toxicity refers to the capacity of a substance or composition to be harmful or poisonous to a cell, tissue organism or cellular environment.
  • Low toxicity refers to a reduced capacity of a substance or composition to be harmful or poisonous to a cell, tissue organism or cellular environment.
  • Such reduced or low toxicity may be relative to a standard measure, relative to a treatment or relati ve to the absence of a treatment.
  • conjugates or formulations of the present disclosure may have lower toxicity than the active agent moiety Z administered alone.
  • DM1 their toxicity is lower than DM1 administered alone.
  • Toxicity may further be measured relative to a subject’s weight loss where weight loss over 15%, over 20% or over 30% of the body weight is indicative of toxicity.
  • Other metrics of toxicity may also be measured such as patient presentation metrics including lethargy and general malaiase.
  • Neutropenia, thrombopenia, white blood cell (WBC) count, complete blood cell (CBC) count may also be metrics of toxicity.
  • Pharmacologic indicators of toxicity include elevated aminotransferases (AST/ALT) levels, neurotoxicity, kidney damage, Gl damage and the like.
  • conjugates or formulations of the present disclosure do not cause a significant change of a subject’s body weight.
  • the body weight loss of a subject is less about 30%, about 20%, about 15%, about 10%, or about 5% after treatment with conjugates or formulations of the present disclosure.
  • conjugates or formulations of the present disclosure do not cause a significant increase of a subject’s AST/ALT levels.
  • the AST or ALT level of a subject is increased by less than about 30%, about 20%, about 15%, about 10%, or about 5% after treatment with conjugates or formulations of the present disclosure.
  • conjugates or formulations of the present disclosure do not cause a significant change of a subject’s CBC or WBC count after treatment with conjugates or formulations of the present disclosure.
  • conjugates or formulations of the present disclosure are combined with at least one additional active agent.
  • the active agent may be any suitable drug.
  • the conjugates and the at least one additional active agent may be administered simultaneously, sequentially, or at any order.
  • Tire conjugates and the at least one additional active agent may be administered at different dosages, with different dosing frequencies, or via different routes, whichever is suitable,
  • the additional active agent may he selected from any active agent described herein such as a drag for treating cancer. It may also be a cancer symptom relief drug.
  • Non- limiting examples of symptom relief drugs include: octreotide or lanreotide; interferon, cypoheptadine or any other antihistamines.
  • conjugates or formulations of the present disclosure do not have drug-drug interference with the additional active agent.
  • conjugates or formulations of the present disclosure do not inhibit cytochrome P450 (CYP) isozymes.
  • CYP isozymes may include CYP3A4 Midazolam, CYP3A4 Testosterone, CYP2C9, CYP2D6, CYP1A2, CYP2C8, CYP2B6, and CYP2C19.
  • the additional active agent may be administered concomitantly with conjugates or fonnulations of the present disclosure.
  • conjugates or fonnulations of the present disclosure may be combined with a moderate dose of chemotherapy agents such as mitomycin C, vinblastine and cisplatin (see Ellis et al, Br J Cancer, vol.71(2): 366-370 (1995), the contents of which are incorporated herein by reference in their entirety).
  • chemotherapy agents such as mitomycin C, vinblastine and cisplatin
  • a patient may first receive a pharmaceutically effective dose of an unconjugated active agent, followed by a pharmaceutically effective dose of a conjugate comprising the same active agent.
  • conjugates or formulations as described herein or formulations containing the conjugates or fonnulations as described herein can be used for the selective tissue delivery of a therapeutic, prophylactic, or diagnostic agent to an individual or patient in need thereof.
  • conjugates or fonnulations of the present disclosure are used to deliver the payloads to selective tissues. These tissues may be tumor tissues.
  • Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered overtime or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic.
  • PROTACs Proteolysis targeting chimeras
  • These PROTAC molecules are usually conjugates comprising a ligand that binds to a protein of interest (POI ligand) and a ligand that binds to E3 hgase (E3 ligand).
  • Tire POI ligand and E3 ligand are connected through a crosslinker.
  • the PROTACs recuite POI to E3 ligase.
  • Ubiquitin (Ub) is added to the POI Lys residues, The Ub-marked POI is degraded by the proteasome.
  • PROTACs induce the target protein to be degraded instead of (or in addition to) being inhibited. This opens up an alternate way to kill the activity of a protein to enhance the impact on the pathway or to target previously imdruggable targets.
  • the challenges of PROTACs include finding tissue selective E3 ligases (only -600 members of the class).
  • conjugates of the present disclosure induces degradation of a target protein in the tumor cells, such as the R ⁇ 3K protein in the tumor cells.
  • the target protein refers to the protein that is regulated (e.g., its functions or activities are up-regulated or inhibited) by the conjugates of the present disclosure.
  • the target protein of the conjugate is not a client protein of HSP90 and the degradation of the target protein is not driven by HSP90.
  • the target protein of the active agent is a client protein of HSP90 (such as but not limited to HER2) and the degradation of the target protein of the active agent is higher than the degradation achieved by the HSP90-binding targeting ligand alone or than the degradation achieved by the non-HSP9Q-binding binding control.
  • the conjugates of the present disclosure bind to HSP90, which associates with E3 ubiquitin ligases to degrade the target proteins of the payloads if folding is stalled.
  • HSP9Q-binding conjugates comprising PI3K inhibitors can ubiquitinate PI3K and induce the degradation of PI3K.
  • the conjugates of the present disclosure induce the degradation of the target protein of the active agent in cells. In some embodiments, the conjugates of the present disclosure induce the degradation of the target protein and inhibit the activity and/or function of the target protein of the active agent in cells. The degradation of the target protein and the inhibition of the target protein can be measured with any method known in the art. In some embodiments, the cells are tumor cells.
  • the level of degradation of target protein is about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% higher than the degradation achieved by the HSP90-binding targeting ligand alone or than the degradation achieved by the non-HSP90-binding control.
  • the level of degradation of target protein is about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% as compared to a vehicle or non-treated or other appropriate control.
  • the conjugates of the present disclosure are bifunctional. They induce the degradation of at least one H8P90 client protein, such as HER2, and they induce the degradatoin of the target protein of the active agent, wherein the target protein of the active agent is not an HSP90 client protein.
  • the conjguates of the present disclosure induce degradation of PI3K in cells.
  • conjugates of the presnet disclosure induce degradation of PI3K and inhibit the activity and/or function of P13K in tumor cells.
  • the degradation of PI3K and the inhibition of PI3K can be measured in any method known in the art.
  • the cells are tumor cells.
  • the linkers of the conjugates are not deavabie.
  • the conjugates have low permeability .
  • kits and devices for conveniently and/or effectively carrying out methods of the present disclosure.
  • kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject(s) and/or to perform multiple experiments.
  • kits for inhibiting tumor cell growth in vitro or in vivo comprising a conjugate and/or particle of the present disclosure or a combination of conjugates and/or formulations of the present disclosure, optionally in combination with any other active agents.
  • the kit may further comprise packaging and instructions and/or a delivery- agent to form a formulation composition.
  • the delivery agent may comprise a saline, a buffered solution, or any delivery ' agent disclosed herein.
  • the amount of each component may be varied to enable consistent, reproducible higher concentration saline or simple buffer formulations.
  • the components may also be varied in order to increase the stability of the conjugates and/or formulations in the buffer solution over a period of time and/or under a variety' of conditions.
  • the present disclosure provides for devices which may incorporate conjugates and/or formulations of the present disclosure. These devices contain in a stable formulation available to be immediately delivered to a subject in need thereof, such as a human patient. In some embodiments, the subject has cancer.
  • Non-limiting examples of the devices include a pump, a catheter, a needle, atransdermal patch, a pressurized olfactory delivery device, iontophoresis devices, multi-layered microfluidic devices.
  • the devices may be employed to deliver conjugates and/or formulations of the present disclosure according to single, multi- or split-dosing regiments.
  • the devices may be employed to deliver conjugates and/or formulations of the present disclosure across biological tissue, intradermal, subcutaneously, or intramuscularly,
  • conjugate is also meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present disclosure that contain asymmetrically 7 substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C :::: N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Examples prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H ⁇ and 2H- isoindole, and 1H ⁇ and 2H-pyrazole.
  • Tautomeric fonns can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.
  • the compounds and salts of the present disclosure can be prepared in combination with solvent or w ater molecules to form solvates and hydrates by routine methods.
  • subject refers to any organism to which the conjugates may be administered, e.g., for experimental, therapeutic, diagnostic, and/or prophylactic purposes.
  • Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, guinea pigs, cattle, pigs, sheep, horses, dogs, cats, hamsters, lamas, non-human primates, and humans).
  • treating can include preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder or condition; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
  • Treating the disease, di sorder, or condition can include amel iorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected. such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
  • a “target”, as used herein, shall mean a site to which targeted constructs bind.
  • a target may be either in vivo or in vitro.
  • a target may be cancer cells found in leukemias or tumors (e.g., tumors of the brain, lung (small cell and non-small cell), ovary, prostate, breast and colon as well as other carcinomas and sarcomas).
  • a target may refer to a molecular structure to which a targeting moiety or ligand binds, such as a hapten, epitope, receptor, dsDNA fragment, carbohydrate or enzyme.
  • a target may be a type of tissue, e.g., neuronal tissue, intestinal tissue, pancreatic tissue, liver, kidney, prostate, ovary, lung, bone marrow, or breast tissue.
  • the “target cells” that may serve as the target for the method or conjugates or formulations are generally animal cells, e.g., mammalian cells.
  • the present method may be used to modify cellular function of living cells in vitro, i.e., in cell culture, or in vivo , in which the cells form part of or otherwise exist in animal tissue.
  • the target cells may include, for example, the blood, lymph tissue, cells lining the alimentary canal, such as the oral and pharyngeal mucosa, cells forming the villi of the small intestine, cells lining the large intestine, cells lining the respirator ⁇ ' system (nasal passages/lungs) of an animal (which may be contacted by inhalation of the subject disclosure), dermal/epidermal cells, cells of the vagina and rectum, cells of internal organs including cells of the placenta and the so-called blood/brain barrier, etc.
  • a target cell expresses at least one type of HSP90.
  • a target cell can be a cell that expresses an HSP90 and is targeted by a conjugate described herein, and is near a cell that is affected by release of the acti ve agent of the conjugate.
  • a blood vessel expressing an HSP90 that is in proximity to a tumor may be the target, while the active agent released at the site will affect the tumor.
  • the term "therapeutic effect” is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance.
  • the term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or pre vention of disease, disorder or condition in the enhancement of desirable physical or mental development and conditions in an animal, e.g., a human.
  • modulation is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart. The modulation is generally compared to a baseline or reference that can be internal or external to the treated entity.
  • Parenteral administration means administration by any method other than through the digestive tract (enteral) or non-in vasive topical routes.
  • parenteral administration may include administration to a patient intravenously, intrademially, intraperitoneally, intrapleurally, intratracheally, intraossiously, intracerebrally, intrathecally, intramuscularly, subcutaneously, subjunctivally, by injection, and by infusion.
  • Topical administration means the non-invasive administration to the skin, orifices, or mucosa.
  • Topical administration can be delivered locally, i.e., the therapeutic can provide a local effect in the region of delivery without systemic exposure or with minimal systemic exposure.
  • Some topical formulations can provide a systemic effect, e.g., via adsorption into the blood stream of the individual.
  • Topical administration can include, but is not limited to, cutaneous and transdemial administration, buccal administration, intranasal administration, intravaginal administration, intravesical administration, ophthalmic administration, and rectal administration.
  • Enteral administration means administration via absorption through the gastrointestinal tract. Enteral administration can include oral and sublingual administration, gastric administration, or rectal administration.
  • “Pulmonary administration”, as used herein, means administration into the lungs by inhalation or endotracheal administration.
  • inhalation refers to intake of air to the alveoli. The intake of air can occur through the mouth or nose.
  • a “therapeutically effective amount” is at least the minimum concentration required to effect a measurable improvement or pre vention of at least one symptom or a particular condition or disorder, to effect a measurable enhancement of life expectancy, or to generally improve patient quality of life.
  • the therapeutically effective amount is thus dependent upon the specific biologically active molecule and the specific condition or disorder to be treated.
  • Therapeutically effective amounts of many active agents, such as antibodies, are known in the art.
  • bioactive agent and ‘ ‘ active agent”, as used interchangeably herein, include, without limitation, physiologically or pharmacologically active substances that act locally or systemically in the body.
  • a bioactive agent is a substance used for the treatment (e.g., therapeutic agent), prevention (e.g., prophylactic agent), diagnosis (e.g., diagnostic agent), cure or mitigation of disease or illness, a substance which affects the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • prodrug refers to an agent, including a small organic molecule, peptide, nucleic acid or protein, that is converted into a biologically active form in vitro and/or in vivo.
  • Prodrugs can be useful because, in some situations, they may he easier to administer than the parent compound (the active compound). For example, a prodrug may be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. A prodrug may also be less toxic than the parent. A prodrug may be con verted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Harper, N.J. (1962) Drug Latentiation in Tucker, ed.
  • biocompatible refers to a material that along with any metabolites or degradation products thereof that are generally non-toxic to the recipient and do not cause any significant adverse effects to the recipient.
  • biocompatible materials are materials which do not elicit a significant inflammatory or immune response when administered to a patient.
  • biodegradable generally refers to a material that will degrade or erode under physiologic conditions to smaller units or chemical species that are capable of being metabolized, eliminated, or excreted by the subject.
  • the degradation time is a function of composition and morphology. Degradation times can be from hours to weeks.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio, in accordance with the guidelines of agencies such as the U.S. Food and Drug Administration.
  • a “pharmaceutically acceptable carrier”, as used herein, refers to all components of a pharmaceutical formulation that facilitate the delivery of the composition in vivo.
  • Pharmaceutically acceptable carriers include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof.
  • molecular weight generally refers to the mass or average mass of a material. If a polymer or oligomer, the molecular weight can refer to the relative average chain length or relative chain mass of the hulk polymer, in practice, the molecular weight of polymers and oligomers can be estimated or characterized in various ways including gel permeation chromatography (GPC) or capillary viscometry. GPC molecular weights are reported as the weight-average molecular weight (M w ) as opposed to the number-average molecular weight (M B ). Capillary viscometry provides estimates of molecular weight as the inherent viscosity determined from a dilute polymer solution using a particular set of concentration, temperature, and solvent conditions.
  • small molecule generally refers to an organic molecule that is less than 2000 g/mol in molecular weight, less than 1500 g/mol, less than 1000 g/mol, less than 800 g/mol, or less than 500 g/mol. Small molecules are non-poly meric and/or non-oligomeric.
  • hydrophilic refers to substances that have strongly polar groups that readily interact with water.
  • hydrophobic refers to substances that lack an affinity for water; tending to repel and not absorb water as well as not dissol ve in or mix with water.
  • lipophilic refers to compounds having an affinity for lipids.
  • amphiphilic refers to a molecule combining hydrophilic and lipophilic (hydrophobic) properties.
  • Amphiphilic material refers to a material containing a hydrophobic or more hydrophobic oligomer or polymer (e.g., biodegradable oligomer or polymer) and a hydrophilic or more hydrophilic oligomer or polymer.
  • targeting moiety refers to a moiety that binds to or localizes to a specific locale.
  • the moiety may be, for example, a protein, nucleic acid, nucleic acid analog, carbohydrate, or small molecule.
  • the locale may be a tissue, a particular cell type, or a subcellular compartment, in some embodiments, a targeting moiety can specifically bind to a selected molecule.
  • reactive coupling group refers to any chemical functional group capable of reacting with a second functional group to form a covalent bond.
  • the selection of reactive coupling groups is within the ability of those in the art.
  • Examples of reactive coupling groups can include primary amines (-NH2) and amine-reactive linking groups such as isothiocyanates, isocyanates, acyl azides, NITS esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, aryl halides, imidoesters, carbodiimides, anhydrides, and fluorophenyl esters.
  • -NH2 primary amines
  • amine-reactive linking groups such as isothiocyanates, isocyanates, acyl azides, NITS esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates,
  • reactive coupling groups can include aldehydes (-COH) and aldehyde reactive linking groups such as hydrazides, alkoxyamines, and primary amines.
  • reactive coupling groups can include thiol groups (-SH) and sulfhydryl reactive groups such as maleimides, haloacetyls, and pyridyl disulfides.
  • reactive coupling groups can include photoreactive coupling groups such as aryl azides or diazirines.
  • the coupling reaction may include the use of a catalyst, heat, pH buffers, light, or a combination thereof,
  • protective group refers to a functional group that can be added to and/or substituted for another desired functional group to protect the desired functional group from certain reaction conditions and selectively removed and/or replaced to deprotect or expose the desired functional group.
  • Protective groups are known to the skilled artisan. Suitable protective groups may include those described in Greene and Wilts, Protective Groups m Organic Synthesis, (1991). Acid sensitive protective groups include dimethoxytrityl (DMT), tert- butylcarbamate (tBoc) and trifluoroacetyl (tFA).
  • Base sensitive protective groups include 9- fluorenylmethoxycarbonyl (Fmoc), isobutyrl (iBu), benzoyl (Bz) and phenoxyacetyl (pae).
  • Other protective groups include acetamidomethyl, acetyl, tert- amyloxycarbonyl, benzyl, benzyloxy carbonyl, 2-(4-biphsnylyl)-2-propy!oxycarbony3, 2- bromobenzyloxycarbonyl, tert-butyb tert-butyloxycarbonyl, 1-carbobenzoxamido- 2,2.2- trifluoroethyl, 2,6-dichlorobenzyl, 2-(3,5-dimethoxyphenyl)-2- propyloxycarbonyl, 2,4- dinitrophenyl, dithiasuccinyl, formyl, 4- methoxybenzenesulfonyl, 4-methoxybenzy
  • activated ester refers to alkyl esters of carboxylic acids where the alkyl is a good leaving group rendering the carbonyl susceptible to nucleophilic atack by molecules bearing amino groups. Activated esters are therefore susceptible to aminolysis and react with amines to form amides. Activated esters contain a carboxylic acid ester group -CO 2 R where R is the leaving group.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), 20 or fewer, 12 or fewer, or 7 or fewer.
  • cycloalkyls have from 3-10 carbon atoms in their ring structure, e.g., have 5, 6 or 7 carbons in the ring structure.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the later of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents include, hut are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxy carbonyl, formyl, or an acyl), tliiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a hosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyk aralkyl, or an aromatic or heteroaromatic moiety.
  • carbonyl such as a carboxyl, alkoxy carbonyl, formyl, or an acyl
  • tliiocarbonyl such as a thio
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, or from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. In some embodiments, alkyl groups are lower alkyls. In some embodiments, a substituent designated herein as alkyl is a lower alkyl. [0249] It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phospboryl (including phosphorate and ph osphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Cyeloalkyls can be substituted in the same manner.
  • heteroalkyl refers to straight or branched chain, or cyclic carbon-containing radicals, or combinations thereof, containing at least one heteroatom. Suitable h eteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quatemized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the " alkyithio" moiety is represented by one of -S-alkyl, -S-alkenyl, and -S-alkynyl.
  • Representative alkylthio groups include methylthio, and ethylthio.
  • the temi “alkylthio” also encompasses cycloalkyl groups, alkene and cycloalkane groups, and alkyne groups.
  • Arylthio refers to aryl or heteroaryl groups. Alkylthio groups can be substituted as defined above for alkyl groups.
  • alkenyl and alkynyi refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkoxyi refers to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyi groups include methoxy, ethoxy, propyloxy, and tert-butoxy.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyi, such as can he represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.
  • Aroxy can be represented by -0-aryl or O-heteroaryL wherein aryl and heteroaryl are as defined below.
  • alkoxy and aroxy groups can be substituted as described above for alkyl [0254]
  • amine and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula: wherein R9, R10, and R' 10 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R8 or R9 and R10 taken together with the N atom to winch they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
  • R9 or R10 can be a carbonyl, e,g., R9>, R10 and the nitrogen together do not form an imide.
  • the term '‘amine” does not encompass amides, e.g., wherein one of R9 and R10 represents a carbonyl, in additional embodiments, R9 and R10 (and optionally R " 10) each independently represent a hydrogen, an alkyl or cycloalkly, an alkenyl or cycloalkenyl, or alkynyl.
  • alkylam ine as used herein means an amine group, as defined above, having a substituted (as described above tor alkyl) or unsubstituted alkyl attached thereto, i.e., at least one of R9 and R10 is an alkyl group.
  • amino is art-recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula: wherein R9 and R10 are as defined above.
  • Aryl refers to C5-C10-membered aromatic, heterocyclic, fused aromatic, fused heterocyclic, biaromatic, or bihetereocyclic ring systems.
  • aryl includes 5-, 6-, 7-, 8-, 9-, and 10-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ting structure may also be referred to as “and heterocycles” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino (or quaternized amino), nitro, suifhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, suifonyl, sulfonamide, ketone, aldehyde, ester, heterocydyl, aromatic or heteroaromatic moieties, -CF3 -CN; and combinations thereof.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., “fused rings”) wherein at least one of the rings is aromatic, e.g . the other cycl ic ring or rings can be cycloalkyls, cycloalkenyls, eycloalkynyls, aryls and/or heterocycles.
  • heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzotliiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazohnyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H ,6H -1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H- indazolyl, indolenyi, indolinyl, in
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • carbocyde refers to an aromatic or non- aromatic ring in which each atom of the ring is carbon.
  • Heterocycle refers to a cyclic radical attached via a ring carbon or nitrogen of a monocyclic or bicyciic ring containing 3-10 ring atoms, for example, from 5-6 ring atoms, consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O , (C1-C10) alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents.
  • heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyi, benztriazolyl, benztetrazolyl, benzisoxazolyl.
  • benzisothiazolyl benzimidazolinyl, carbazolyl, 4aH -carbazolyl, earbolinyl, chromanyl, cbromenyl, einnolinyl, decahydroquinolinyl, 2H ,6 H-1,5,2-dithiazinyl, dihydrofuro[2,3-6]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1/7-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isomdolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxy
  • Heterocyclic groups can optionally be substituted with one or more substituents at one or more positions as defined above for alkyl and aryl, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, am ido, phosphate, pbosphonate, phosphinate, carbonyl, carboxyl, silyl ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, and -CN.
  • substituents at one or more positions as defined above for alkyl and aryl, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydr
  • carbonyl is art-recognized and includes such moieties as can be represented by the general formula: wherein X is a bond or represents an oxygen or a sulfur, and R 11 represents a hydrogen, an alkyl, a cycloalkyl, an alkenyl, a cycloalkenyl, or an alkynyl, R' 11 represents a hydrogen, an alkyl, a cycloalkyl, an alkenyl, a cycloalkenyl, or an alkynyl. Where X is an oxygen and R 11 or R’ 11 is not hydrogen, the formula represents an "ester".
  • monoester refers to an analog of a dicarboxylic acid wherein one of the carboxylic acids is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or salt of a carboxylic acid.
  • monoesters include, but are not limited to, to monoesters of succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, oxalic and maleic acid.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Examples of heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Other useful heteroatoms include silicon and arsenic.
  • nitro means -NO2; the term “halogen” designates -F, -Cl, -Br or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH: and the term “sulfonyl” means -SO2-.
  • sulfhydryl means -SH; the term “hydroxyl” means -OH: and the term “sulfonyl” means -SO2-.
  • '‘substituted” as used herein, refers to all permissible substituents of the compounds described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyeiic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, for example, 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats .
  • substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted am ino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, poly
  • Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that “substitution” or “substituted” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, or elimination.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyeiic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalky], ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, each of which optionally is substituted with one or more suitable substituents.
  • the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, earboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, wherein each of the alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, aryialkyl, carbamate, earboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfmyl, sulf
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryi, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkyithio, sulfonyl, suifonamido, ketone, aldehyde, thioketone, ester, heterocyclyl, - CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, alkylthio, oxo, acylalkyl, earboxy esters, carboxamido, aeyloxy, am inoalkyl, alkylaniin
  • copolymer generally refers to a single polymeric material that is comprised of two or more different monomers.
  • the copolymer can be of any form, for example, random, block, or graft.
  • the copolymers can have any end- group, including capped or acid end groups.
  • polypeptide generally refer to a polymer of amino acid residues. As used herein, the tenn also applies to amino acid polymers in which one or more amino acids are chemical analogs or modified derivati ves of corresponding naturally-occurring amino acids or are unnatural amino acids.
  • protein refers to a polymer of amino acids linked to each other by peptide bonds to form a polypeptide for which the chain length is sufficient to produce tertiary and/or quaternary structure.
  • protein excludes small peptides by definition, the small peptides lacking the requisite higher- order structure necessary to be considered a protein.
  • nucleic acid refers to a deoxyribonucleotide or ribonucleotide polymer, in linear or circular conformation, and in either single- or double-stranded form. These terms are not to be construed as limiting with respect to the length of a polymer.
  • the terms can encompass known analogs of natural nucleotides, as well as nucleotides that are modified in the base, sugar and/or phosphate moieties (e.g., phosphorothioate backbones).
  • nucleic acid is a term of art that refers to a string of at least two base-sugar-phosphate monomeric units. Nucleotides are the monomeric units of nucleic acid polymers. The term includes deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in the form of a messenger RNA, antisense, plasmid DNA, parts of a plasmid DNA or genetic material derived from a virus.
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • nucleic acids refers to a string of at least two base -sugar- phosphate combinations. Natural nucleic acids have a phosphate backbone. Artificial nucleic acids may contain other types of backbones, but contain the same bases as natural nucleic acids. The term also includes PNAs (peptide nucleic acids), phosphorothioates, and other variants of the phosphate backbone of native nucleic acids.
  • a "functional fragment" of a protein, polypeptide or nucleic acid is a protein, polypeptide or nucleic acid wh ose sequence is not identical to the full-length protein, polypeptide or nucleic acid, yet retains at least one function as the full-length protein, polypeptide or nucleic acid.
  • a functional fragment can possess more, fewer, or the same number of residues as the corresponding native molecule, and/or can contain one or more amino acid or nucleotide substitutions.
  • the DNA binding function of a polypeptide can be determined, for example, by filter-binding, electrophoretic mobility shift, or immunoprecipitation assays. DNA cleavage can be assayed by gel electrophoresis. The ability of a protein to interact with another protein can be de termined, for example, by co-immunoprecipitation, two-hybrid assays or complementation, e.g., genetic or biochemical ⁇ See, for example, Fields et al. (1989) Nature 340:245-246; U S. Patent No. 5,585,245 and PCT WO 98/44350.
  • linker refers to a carbon chain that can contain heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) and which may be 1, 2, 3, 4, 5, 6, 7,
  • Linkers may be substituted with various substituents including, but not limited to, hydrogen atoms, alkyl, alkenyl, alkynl, amino, alkylamino, dialkylamino, trialkyl amino, hydroxyl, alkoxy, halogen, and, heterocyclic, aromatic heterocyclic, cyano, amide, carbamoyl, carboxylic acid, ester, thioether, alkylthioether, thiol, and ureido groups.
  • linkers include, but are not limited to, pH-sensitive linkers, protease deavable peptide linkers, nuclease sensitive nucleic acid linkers, lipase sensitive lipid linkers, glycosidase sensitive carbohydrate linkers, hypoxia sensitive linkers, photo-eleavable linkers, heat-labile linkers, enzyme cleavable linkers (e.g., esterase cleavable linker), ultrasound-sensitive linkers, and x-ray cleavable linkers.
  • linkers include, but are not limited to, pH-sensitive linkers, protease deavable peptide linkers, nuclease sensitive nucleic acid linkers, lipase sensitive lipid linkers, glycosidase sensitive carbohydrate linkers, hypoxia sensitive linkers, photo-eleavable linkers, heat-labile linkers, enzyme cleavable linkers (e.g., esterase cleavable linker), ultrasound-sensitive linkers, and x-ray
  • salts refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a variety of salts with various inorganic and organic acids.
  • Tire acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisuifate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i
  • Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts,
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • a pharmaceutically acceptable salt can be derived from an acid selected from 1 -hydroxy -2 -naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutane acid, 4-acetam idobenzoie acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid (decanoie acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cydamic acid, dodecylsuifuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid,
  • bioavailable is art-recognized and refers to a form of the subject disclosure that allows for it, or a portion of the amount administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject or patient to whom it is administered.
  • the conjugates of the disclosure may be prepared using any convenient methodology.
  • the conjugates are constructed from their individual components, targeting moiety, in some cases a linker, and active agent moiety.
  • the components can be covalently bonded to one another through functional groups, as is known in the art, where such functional groups may be present on the components or introduced onto the components using one or more steps, e.g., oxidation reactions, reduction reactions, cleavage reactions and the like.
  • Functional groups that may be used in covalently bonding the components together to produce the pharmaceutical conjugate include: hydroxy, sulfhydryl, amino, and the like.
  • the particular portion of the different components that are modified to provide for covalent linkage will be chosen so as not to substantially adversely interfere with that components desired binding activity, e.g., for the active agent moiety, a region that does not affect the target binding activity will be modified, such that a sufficient amount of the desired drug activity is preserved.
  • certain moieties on the components may be protected using blocking groups, as is known in the art, see, e.g., Green & Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons) (1991).
  • the conjugate can be produced using known combinatorial methods to produce large libraries of potential conjugates which may then be screened for identification of a bifunctional, molecule with the pharmacokinetic profile.
  • the conjugates may be produced using medicinal chemistry and known structure-activity relationships for the targeting moiety and the active agent moiety. In particular, this approach will provide insight as to where to join the two moieties to the linker.
  • EXAMPLE 2 BRD4 binding assay
  • a fluorescence polarization (FP) binding assay was used to determine the binding affinities of the compounds of the present disclosure to Human Recombinant B R D4 (44-460) protein, using methods known in the art.

Landscapes

  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des conjugués d'un agent actif fixés à une fraction de ciblage, telle qu'une fraction de liaison à la protéine de choc thermique 90 (HSP90), par l'intermédiaire d'un lieur, et des formulations comprenant de tels conjugués. L'invention concerne également des procédés de préparation et d'utilisation des conjugués et des formulations de ceux-ci. Dans certains modes de réalisation, l'agent actif est un inhibiteur de bromodomaine et de motif extra-terminal (BET) tel qu'un inhibiteur de protéine 4 contenant un bromodomaine (BRD4).
PCT/US2022/027805 2021-05-05 2022-05-05 Conjugués liés à hsp90 et formulations de ceux-ci WO2022235889A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163184352P 2021-05-05 2021-05-05
US63/184,352 2021-05-05

Publications (1)

Publication Number Publication Date
WO2022235889A1 true WO2022235889A1 (fr) 2022-11-10

Family

ID=83932472

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/027805 WO2022235889A1 (fr) 2021-05-05 2022-05-05 Conjugués liés à hsp90 et formulations de ceux-ci

Country Status (1)

Country Link
WO (1) WO2022235889A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170008904A1 (en) * 2015-07-10 2017-01-12 Arvinas, Inc. Mdm2-based modulators of proteolysis and associated methods of use
WO2020205948A1 (fr) * 2019-04-03 2020-10-08 Tarveda Therapeutics, Inc. Conjugués liés à hsp90 et formulations de ceux-ci

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170008904A1 (en) * 2015-07-10 2017-01-12 Arvinas, Inc. Mdm2-based modulators of proteolysis and associated methods of use
WO2020205948A1 (fr) * 2019-04-03 2020-10-08 Tarveda Therapeutics, Inc. Conjugués liés à hsp90 et formulations de ceux-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PHILIPP M. CROMM, CRAIG M. CREWS: "Targeted Protein Degradation: from Chemical Biology to Drug Discovery", CELL CHEMICAL BIOLOGY , ELSEVIER, AMSTERDAM, NL, vol. 24, no. 9, 1 September 2017 (2017-09-01), AMSTERDAM, NL , pages 1181 - 1190, XP055560970, ISSN: 2451-9456, DOI: 10.1016/j.chembiol.2017.05.024 *

Similar Documents

Publication Publication Date Title
US20220096640A1 (en) Hsp90-targeting conjugates and formulations thereof
JP6602834B2 (ja) 標的化コンジュゲートならびにその粒子及び製剤
US20210000966A1 (en) Hsp90-targeting conjugates and formulations thereof
US20220096646A1 (en) Sstr-targeted conjugates and particles and formulations thereof
US20200078468A1 (en) Neurotensin receptor binding conjugates and formulations thereof
US20200009262A1 (en) Targeted constructs and formulations thereof
US11510910B2 (en) HSP90 targeted conjugates and particles and formulations thereof
US20180296685A1 (en) Targeted constructs and formulations thereof
WO2017210246A2 (fr) Conjugués de pénicillamine et particules et formulations associées
WO2018222987A1 (fr) Constructions ciblées
KR20190077476A (ko) 상글리페린 거대고리 유사체의 항암 화합물로서의 용도
JP2018518509A (ja) 白金化合物、組成物及びその使用
WO2022047008A1 (fr) Conjugués liés à hsp90 et formulations de ceux-ci
JP2018519283A (ja) 標的化コンジュゲートならびにその粒子および製剤
WO2022235889A1 (fr) Conjugués liés à hsp90 et formulations de ceux-ci
US20200237746A1 (en) Hsp90 targeted conjugates and particle formulations thereof
KR20220062363A (ko) 암 표적성 약물 전달체로서의 인지질 에테르 접합체
US20220031853A1 (en) Hsp90-targeting conjugates and formulations thereof
CN114096279A (zh) Sstr靶向缀合物及其制剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22799569

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22799569

Country of ref document: EP

Kind code of ref document: A1