WO2021239117A1 - Modified proteins and protein degraders - Google Patents

Modified proteins and protein degraders Download PDF

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Publication number
WO2021239117A1
WO2021239117A1 PCT/CN2021/096782 CN2021096782W WO2021239117A1 WO 2021239117 A1 WO2021239117 A1 WO 2021239117A1 CN 2021096782 W CN2021096782 W CN 2021096782W WO 2021239117 A1 WO2021239117 A1 WO 2021239117A1
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WIPO (PCT)
Prior art keywords
optionally substituted
ddb1
protein
alkyl
heteroaryl
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PCT/CN2021/096782
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English (en)
French (fr)
Inventor
Jing Liu
Michael Bruno Plewe
Matthew Randolph Lee
Xiaoran HAN
Liqun Chen
Chengwei Zhang
Jialiang Wang
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Cullgen Shanghai Inc
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Cullgen Shanghai Inc
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Priority to JP2022573579A priority Critical patent/JP2023529099A/ja
Priority to CN202180058377.0A priority patent/CN116472292A/zh
Priority to EP21812627.4A priority patent/EP4157888A4/en
Priority to US17/496,628 priority patent/US20230057177A1/en
Publication of WO2021239117A1 publication Critical patent/WO2021239117A1/en
Anticipated expiration legal-status Critical
Priority to US18/361,422 priority patent/US20240066136A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • modified proteins and protein-ligand complexes are useful for biotechnology applications such as selective degradation of a target protein, molecular glues, or anti-microbial drugs.
  • ligands that can bind to DD1.
  • the DDB1 binding ligands are useful for biotechnology applications such as selective degradation of a target protein, molecular glues, or anti-microbial drugs
  • ligand-DNA damage-binding protein 1 (DDB1) complexes formed by binding a DDB1 protein directly to a ligand, the ligand comprising a DDB1 binding moiety.
  • the DDB1 binding moiety is bound to a binding region on the DDB1 protein.
  • the binding region on the DDB1 protein comprises a beta propeller C (BPC) domain.
  • the binding region on the DDB1 protein comprises a top face of the BPC domain.
  • the binding region on the DDB1 protein comprises one or more of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • DDB1 residues ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU78
  • one or more of the following DDB1 residues are involved in the binding between the DDB1 protein and the ligand: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • the binding between the DDB1 binding moiety and the DDB1 protein is non-covalent.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) below 100 ⁇ M, a Kd below 90 ⁇ M, a Kd below 80 ⁇ M, a Kd below 70 ⁇ M, a Kd below 60 ⁇ M, below 50 ⁇ M, a Kd below 45 ⁇ M, a Kd below 40 ⁇ M, a Kd below 35 ⁇ M, a Kd below 30 ⁇ M, a Kd below 25 ⁇ M, a Kd below 20 ⁇ M, a Kd below 15 ⁇ M, a Kd below 14 ⁇ M, a Kd below 13 ⁇ M, a Kd below 12 ⁇ M, a Kd below 11 ⁇ M, a Kd below 10 ⁇ M, a Kd below 9 ⁇ M, a Kd below 8 ⁇ M, a
  • Kd equilibrium dissoci
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 uM, a Kd from 20-100 uM, or a Kd > 100 uM.
  • the binding between the DDB1 binding moiety and the DDB1 protein is covalent.
  • the DDB1 ligand is a small molecule. In some embodiments, the DDB1 ligand is synthetic.
  • the DDB1 binding moiety comprises a structure of Formula (IIa) : Formula (IIa) .
  • F 2 is heteroaryl.
  • F 2 is a five membered or six membered ring heteroaryl.
  • F2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.
  • the DDB1 binding moiety comprises a structure of Formula (IIb) : Formula (IIb) , wherein A 4 and A 5 are each independently CR 12 , S, N, or O, wherein at least one of A 4 or A 5 is N, O, or S. In some embodiments, A 4 is N and A 5 is S. In some embodiments, the DDB1 binding moiety comprises the structure wherein the wavy line indicates an optional point of attachment to a linker or a target protein binding moiety.
  • R 12 at each occurrence, is independently selected from -NO 2 , halogen, methyl, halomethyl, phenyl, isopropyl, cyclopropyl, SO 2 CH 3 , or -CN.
  • R c is H, CH 3 , isopropyl, or cyclopropyl.
  • q is 1 or 2.
  • s is 1 or 2.
  • the DDB1 binding moiety comprises any of compounds B-1 to B-176 as shown in Table 1.
  • the DDB1 binding moiety comprises or a pharmaceutically acceptable salt thereof. In some embodiments, the DDB1 binding moiety comprises or a pharmaceutically acceptable salt thereof. In some embodiments, the DDB1 binding moiety comprises or a pharmaceutically acceptable salt thereof. In some embodiments, the DDB1 binding moiety comprises or a pharmaceutically acceptable salt thereof. In some embodiments, a DDB1 binding moiety comprises a peptide of Table 3. In some embodiments, a DDB1 binding moiety comprises any one of SEQ ID NOs: 1-7 (e.g.
  • the DDB1 binding moiety is covalently connected to a linker.
  • the linker is a bond.
  • the linker is not a bond.
  • the linker is more than just a bond.
  • Some embodiments include a linker attached DDB1 binding moiety.
  • the linker attached DDB1 binding moiety comprises any of compounds BL-1 to BL-71 as shown in Table 2.
  • the linker is further connected to a target protein binding moiety.
  • the target protein binding moiety binds to a target protein.
  • the target protein binding moiety comprises any of compounds A-1 to A-69 as shown in Table 4.
  • the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the heterobifunctional compound comprises any of compounds D-1 to D-130 as shown in Table 5.
  • the complex is formed in vivo. In some embodiments, the complex is formed in vitro.
  • a DNA damage-binding protein 1 (DDB1) protein directly bound to a ligand comprising a DDB1 binding moiety.
  • the DDB1 binding moiety binds to a binding region on the DDB1 protein.
  • the binding region on the DDB1 protein comprises a beta propeller C (BPC) domain.
  • the binding region on the DDB1 protein comprises a top face of the BPC domain.
  • the binding region on the DDB1 protein comprises one or more of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • DDB1 residues ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU78
  • the DDB1 protein is directly bound to the ligand by a non-covalent interaction between the DDB1 protein and the ligand.
  • one or more of the following DDB1 residues are involved in the non-covalent interaction between the DDB1 protein and the ligand: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) below 100 ⁇ M, a Kd below 90 ⁇ M, a Kd below 80 ⁇ M, a Kd below 70 ⁇ M, a Kd below 60 ⁇ M, below 50 ⁇ M, a Kd below 45 ⁇ M, a Kd below 40 ⁇ M, a Kd below 35 ⁇ M, a Kd below 30 ⁇ M, a Kd below 25 ⁇ M, a Kd below 20 ⁇ M, a Kd below 15 ⁇ M, a Kd below 14 ⁇ M, a Kd below 13 ⁇ M, a Kd below 12 ⁇ M, a Kd below 11 ⁇ M, a Kd below 10 ⁇ M, a Kd below 9 ⁇ M, a Kd below 8 ⁇ M, a Kd below 7 ⁇ M, a Kd below 6 ⁇ M, a Kd below 5 ⁇ M
  • Kd
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 uM, a Kd from 20-100 uM, or a Kd >100 uM.
  • the ligand is a small molecule.
  • the ligand comprises a targeted protein degrader.
  • the ligand is synthetic.
  • the ligand and/or the DDB1 binding moiety comprises the structure described herein.
  • the DDB1 binding moiety is covalently connected to a linker.
  • the linker is a bond. In some embodiments, the linker is more than just a bond.
  • the linker is further connected to a target protein binding moiety.
  • the target protein binding moiety binds to a target protein.
  • ligands comprising a DNA damage-binding protein 1 (DDB1) binding moiety.
  • the DDB1 binding moiety is covalently connected through a linker to a target protein binding moiety.
  • the DDB1 binding moiety binds to a DDB1 protein.
  • the DDB1 binding moiety binds to a binding region on the DDB1 protein.
  • the binding between the DDB1 binding moiety and the DDB1 protein is non-covalent.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 uM, a Kd from 20-100 uM, or a Kd > 100 uM.
  • the ligand is a small molecule.
  • the ligand comprises a targeted protein degrader.
  • the ligand is synthetic.
  • the DDB1 binding moiety comprises a structure of Formula (IIa) : Formula (IIa) .
  • F 2 is heteroaryl.
  • F 2 is a five membered or six membered ring heteroaryl.
  • F2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.
  • the DDB1 binding moiety comprises a structure of Formula (IIb) : Formula (IIb) , wherein A 4 and A 5 are each independently CR 12 , S, N, or O, wherein at least one of A 4 or A 5 is N, O, or S. In some embodiments, A 4 is N and A 5 is S. In some embodiments, the DDB1 binding moiety comprises the structure wherein the wavy line indicates a point of attachment to the linker or target protein binding moiety.
  • R 12 at each occurrence, is independently selected from -NO 2 , halogen, methyl, halomethyl, phenyl, isopropyl, cyclopropyl, SO 2 CH 3 , or -CN.
  • R c is H, CH 3 , isopropyl, or cyclopropyl.
  • q is 1 or 2.
  • s is 1 or 2.
  • the DDB1 binding moiety comprises any of compounds B-1 to B-176 as shown in Table 1.
  • the DDB1 binding moiety comprises or a pharmaceutically acceptable salt thereof. In some embodiments, the DDB1 binding moiety or a pharmaceutically acceptable salt thereof. In some embodiments, the DDB1 binding moiety comprises or a pharmaceutically acceptable salt thereof. In some embodiments, the DDB1 binding moiety comprises or a pharmaceutically acceptable salt thereof.
  • the target protein binding moiety binds to a target protein.
  • the target protein binding moiety comprises any of compounds A-1 to A-69 as shown in Table 4.
  • the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the heterobifunctional compound comprises any of compounds D-1 to D-130 as shown in Table 5.
  • the heterobifunctional compound is a degrader of the target protein. In some embodiments, in vivo contact of the ligand with the target protein results in degradation of the target protein.
  • a heterobifunctional ligand comprising a DNA damage-binding protein 1 (DDB1) binding moiety covalently connected through a linker to a target protein binding moiety.
  • DDB1 DNA damage-binding protein 1
  • the subject is a mammal.
  • the subject is a human.
  • the administration is intravenous.
  • the administration is intramuscular.
  • the administration is intrathecal.
  • the administration is subcutaneous.
  • the administration comprises an injection.
  • the administration is oral.
  • the administration is sublingual.
  • the administration is buccal. In some embodiments, the administration is rectal. In some embodiments, the administration is vaginal. In some embodiments, the administration is ocular. In some embodiments, the administration is otic. In some embodiments, the administration is nasal. In some embodiments, the administration is inhalation. In some embodiments, the administration is nebulization. In some embodiments, the administration is cutaneous. In some embodiments, the administration is topical. In some embodiments, the administration is transdermal. In some embodiments, the administration is systemic. In some embodiments, administering the ligand to the subject comprises administering an effective amount of the ligand sufficient to degrade the target protein.
  • the target protein upon administration of the ligand to the subject, is ubiquitinated to form a ubiquitinated target protein.
  • methods for degrading a target protein in a sample comprising: contacting a target protein with a ligand comprising a DNA damage-binding protein 1 (DDB1) binding moiety covalently connected through a linker to a target protein binding moiety.
  • the sample is a biological sample.
  • the biological sample comprises a tissue, a cell, or a biological fluid.
  • the contact is in vitro. In some embodiments, the contact is in vivo.
  • the target protein upon being contacted with the ligand, is ubiquitinated to form a ubiquitinated target protein.
  • the ubiquitinated target protein is degraded.
  • the degradation of the target protein is specific to the target protein.
  • the degradation of the target protein comprises proteasomal degradation.
  • the target protein is degraded by a proteasome.
  • the ligand binds to a DDB1 protein to form a ligand-DDB1 complex.
  • the ligand directly binds to the DDB1 protein through the DDB1 binding moiety of the ligand.
  • the binding between the DDB1 binding moiety and the DDB1 protein is non-covalent. In some embodiments, the binding between the DDB1 binding moiety and the DDB1 protein is covalent.
  • the target protein is ubiquitinated by a ubiquitin E3 ligase complex comprising the DDB1 protein.
  • the ligand e.g. a DDB1 ligand recruits the ubiquitin E3 ligase complex to the target protein via the DDB1 binding moiety. In some embodiments, the ligand is a small molecule.
  • the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the heterobifunctional compound induces the target protein degradation.
  • the ligand comprises a ligand described herein.
  • the target protein comprises any one of a transcription factor, CBP, p300, a kinase, a receptor, a TRK, TrkA, TrkB, TrkC, a cyclin dependent kinase, CDK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, a cyclin, cyclin A, cyclin B, cyclin C, cyclin D, cyclin D1, cyclin D2, cyclin D3, cyclin E, cyclin H, cyclin K, cyclin T, cyclin T1, p25, p35, B7.1, B7, TINFRlm, TNFR2, NADPH oxidase, a partner in an apoptosis pathway, BclIBax, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type
  • a method of treatment comprising: administering to a subject having an infection, a therapeautically effective amount of a heterobifunctional compound comprising a DNA damage-binding protein 1 (DDB1) binding moiety covalently connected to a target protein binding moiety.
  • the infection comprises a viral infection
  • the target protein comprises a viral protein.
  • the compound comprises a ligand described herein.
  • the administration results in ubiquitination and degradation of the target protein.
  • the subject is a human.
  • DDB1 DNA damage-binding protein 1
  • methods of modulating a DNA damage-binding protein 1 (DDB1) protein comprising: contacting a DDB1 protein with a compound comprising a DDB1 binding moiety.
  • the DDB1 binding moiety comprises a structure of Formula (II) , a sturcture of Formula (IIa) , or a structure of Formula (IIb) , or a salt thereof.
  • the compound comprises a compound in Table 1, or a salt thereof.
  • the compound comprises a peptide in Table 3, or a peptide having an amino acid sequence at least 70%identical, at least 75%identical, at least 80%identical, at least 85%identical, at least 90%identical, or at least 95%identical, to a peptide in Table 3.
  • contacting the DDB1 protein with the compound comprises contacting the DDB1 protein with the compound in vitro.
  • contacting the DDB1 protein with the compound comprises delivering the compound to a cell expressing the DDB1 protein.
  • contacting the DDB1 protein with the compound comprises contacting the DDB1 protein with the compound in vivo.
  • contacting the DDB1 protein with the compound comprises administering the compound to a subject.
  • the subject is a human.
  • the compound binds to the DDB1 protein.
  • the contact results in an increase in an amount of the DDB1 protein, relative to a baseline amount.
  • the contact results in a decrease in an amount of the DDB1 protein, relative to a baseline amount.
  • the contact results in an increase in an activity of the DDB1 protein, relative to a baseline activity.
  • the contact results in a decrease in an activity of the DDB1 protein, relative to a baseline activity.
  • a DNA damage-binding protein 1 (DDB1) protein into proximity with a target protein comprising: contacting a DDB1 protein and a target protein with a compound comprising a DDB1 binding moiety and a target protein binding moiety.
  • the compound comprises a ligand described herein.
  • the contact is in vitro.
  • the contact is in vivo.
  • contacting the DDB1 protein and the target protein with the compound comprises delivering the compound to a cell expressing the DDB1 protein and the target protein.
  • contacting the DDB1 protein and the target protein with the compound comprises administering the compound to a subject.
  • the subject is a human.
  • the compound binds to the DDB1 protein and to the target protein.
  • the contact results in an increase in an amount of the target protein, relative to a baseline amount. In some embodiments, the contact results in a decrease in an amount of the target protein, relative to a baseline amount. In some embodiments, the contact results in an increase in an activity of the target protein, relative to a baseline activity. In some embodiments, the contact results in a decrease in an activity of the target protein, relative to a baseline activity.
  • FIG. 1A shows a three-dimensional conformation of protein that includes a DNA damage-binding protein 1 (DDB1) protein in accordance with some embodiments described herein.
  • DDB1 DNA damage-binding protein 1
  • FIG. 1B shows a DDB1 protein bound to a ligand, in accordance with some embodiments.
  • FIG. 2A shows SPR sensorgrams of heterobifunctional compound D-2binding to DDB1.
  • FIG. 2B shows SPR sensorgrams of heterobifunctional compound D-7 binding to DDB1.
  • FIG. 2C shows SPR sensorgrams of heterobifunctional compound D-13 binding to DDB1.
  • FIG. 2D shows SPR sensorgrams of heterobifunctional compound D-48 binding to DDB1.
  • FIG. 2E shows SPR sensorgrams of heterobifunctional compound D-49 binding to DDB1.
  • FIG. 3A shows immunoblots of P300 and CBP protein expressed by LNCaP cells after treatment with heterobifunctional compound D-2 or D-13 at indicated concentrations for 8 hours.
  • FIG. 3B shows immunoblots of P300 and CBP protein expressed by LNCaP cells after treatment with heterobifunctional compound D-7 at indicated concentrations for 8 hours.
  • FIG. 4 shows immunoblots of P300 and CBP protein expressed by LNCaP cells after treatment with heterobifunctional compound D-2 or D-13 at various time points.
  • FIG. 5A shows immunoblots of P300 protein expressed by Calu-1 cells after treatment with heterobifunctional compound D-2 in the presence or absence of Bortezomib (BTZ) , MG-132, or MLN4924.
  • BTZ Bortezomib
  • FIG. 5B shows immunoblots of P300 protein expressed by Calu-1 cells after treatment with heterobifunctional compound D-13 in the presence or absence of BTZ, MG-132, MLN4924, or BL-11.
  • FIG. 6 shows a graph of LNCaP cell viability vs. concentrations of GNE-781, D-2, or D-7.
  • FIG. 7A shows immunoblots of CDK4 and CDK6 protein expressed by Calu-1 cells after treatment with heterobifunctional compound D-44, D-45, D-46, D-47, D-48, or D-49 at indicated concentrations for 16 hours.
  • FIG. 7B shows immunoblots of CDK4 protein expressed by Calu-1 cells after treatment with heterobifunctional compound D-45, D-47, D-48, or D-49 at indicated concentrations for 16 hours.
  • FIG. 8 shows immunoblots of CDK4 and CDK6 protein expressed by Calu-1 cells after treatment with heterobifunctional compound D-48 or D-49 at various time points.
  • FIG. 9 shows immunoblots of a cyclin and a cyclin dependent kinase expressed by Calu-1 cells after treatment with heterobifunctional compound D-118, D-119, or D-120 at indicated concentrations for 16 hours.
  • FIG. 10 shows immunoblots of a cyclin, a cyclin dependent kinase, and phospho-Rb expressed by Calu-1 cells after treatment with various amounts of heterobifunctional compound D-49, D-108, D-110, D-111, D-122, D-123, D-124, D-125, or D-126 for 16 hours .
  • FIG. 11 shows immunoblots of a cyclin, a cyclin dependent kinase, and phospho-Rb expressed by Calu-1 cells after treatment with various amounts of heterobifunctional compound D-49, D-124, D-128, D-129, and D-130 for 16 hours.
  • FIG. 12 showes plots showing cell viability of Calu-1, MDA-MB-453, and MIA PaCa-2 cell lines after treatment with various amounts of compound D-128, D-129, D-130, or Palbociclib for 5 days.
  • FIG. 13 immunoblots of cyclins, cyclin dependent kinases, and phospho-Rb proteins after treatment with 5 uM of heterobifunctional compound D-48 or D-49 for various amounts of time.
  • FIG. 14 shows immunoblots of cyclins, cyclin dependent kinases, and phospho-Rb after treatment with 1.5 uM of heterobifunctional compound D-129 for various amounts of time.
  • compositions comprising a DBB1 binding moiety, a DBB1 binding moiety covalently connected to a linker, and/or a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • DBB1 binding moiety e.g., a DBB1 binding moiety covalently connected to a linker
  • DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • Compounds described herein may be useful for several purposes, including but not limited to use as: 1) antiviral drugs; 2) DDB1 protein level modulators (e.g. increasing or decreasing DDB1 protein levels) ; 3) DDB1 function modulators (e.g.
  • DDB1 activators or inhibitors DDB1 activators or inhibitors
  • molecular glues e.g. increasing a protein-protein interaction between DDB1 and a second protein.
  • the molecular glue function may be useful for affecting activity or protein levels of the second protein.
  • DDB1 protein An example of a DDB1 protein is included in the protein structure shown in FIG. 1A.
  • the DDB1 protein contains 1140 amino acids, and has a mass of 127 kDa.
  • the DDB1 protein may function as a component of an E3 ubiquitin ligase complex.
  • the E3 ubiquitin ligase complex may include CUL4A and CUL4B.
  • the DDB1 protein may serve as a bridge or adaptor and interact with other proteins such as DDB1 and CUL4-associated factors (DCAFs) .
  • the DCAFs may be ubiquitin ligase substrates.
  • ligand-DDB1 complexes are ligand-DDB1 complexes.
  • the ligand-DDB1 complex is formed by non-covalently binding a DDB1 protein directly to a ligand.
  • the ligand comprises a DDB1 binding moiety.
  • the ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the modified protein comprises a DDB1 protein directly bound to a ligand.
  • the ligand comprises a DDB1 binding moiety.
  • the ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the ligand comprises a DDB1 binding moiety.
  • the DDB1 binding moiety is covalently connected through a linker to a target protein binding moiety.
  • Some embodiments comprise administering, to the subject, a ligand comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • FIG. 1B shows a docking model of a DDB1 protein in a complex with a ligand comprising compound B-1 in accordance with some embodiments.
  • the ligand occupies a central cavity of a BPC domain of a DDB1 protein, anchored towards the center of a WD40-motiff by a salt-bridge between the primary amine of LYS723and a nitro group of the ligand and through a Coulombic interaction between the electron-deficient nitrogen of the nitro group and a lone-pair of a nearby water, which is ordered between the backbone carbonyl oxygen atoms of ARG722 and VAL360 as well as the primary amine of LYS723.
  • the pi-faces of the thiazole and amide rest over the VAL360 sidechain, while the amide forms an intermolecular hydrogen bond with the sidechain of ASN1005 and an intramolecular hydrogen bond with the acetate.
  • the sulfur of the thiophene is believed to be geometrically stabilized through a stereoelectronic interaction with the ASN1005 sidechain.
  • the acetate methyl forms dispersion contacts with the ARG722 sidechain and an ordered water.
  • the benzene ring forms dispersion contacts with the sidechains of ALA381, LEU328, PRO358 and VAL1033.
  • the docking model includes compound B-1, other ligands may bind to the DDB1 protein in a similar manner as compound B-1.
  • the binding affinities of specific, non-limiting exemplary heterobifunctional compounds to DDB1 were determined by a surface plasmon resonance (SPR) assay.
  • SPR surface plasmon resonance
  • purified His-DDB1 proteins were immobilized by amine coupling to a density of 11,000-13,000 resonance units (RUs) on a CM5 sensor chip.
  • Sensorgrams were recorded at different concentrations of heterobifunctional compounds in multi-cycle kinetic format. All data were fit to steady state affinity model using Biacore Evaluation Software and gave equivalent dissociation constants (K D ) .
  • Data showed that all exemplary heterobifunctional compounds bind to DDB1 in a concentration-dependent manner, and the binding affinities (K D ) are from 5 ⁇ M to 60 ⁇ M (see FIG. 2, Table 6 and Table 7) .
  • heterobifunctional compounds as described herein could degrade target proteins.
  • Specific exemplary heterobifunctional compounds were characterized in LNCaP and Calu-1 cells.
  • LNCaP cells that express P300/CBP proteins were treated with heterobifunctional compounds disclosed herein (D-2, D-13, or D-7) at indicated concentrations for 8 hours.
  • Cells were collected, lysed and subject to immunoblotting using an antibody specific to P300 or CBP proteins. Vinculin was included as the loading control.
  • DMSO treatment was used as the negative control.
  • P300 and CBP protein levels in LNCaP cells were significantly decreased in a concentration-dependent manner (FIG. 3A and FIG. 3B) .
  • the heterobifunctional compound-mediated p300 and CBP degradation was dependent on the ubiquitin-proteasome system and cullin E3 ligase.
  • the degradation induced by D-2 or D-13 was compromised by co-administration of a proteasome inhibitor, MG-132 or bortezomib (BTZ) , or a cullin RING E3 ubiquitin ligase (CRL) neddylation inhibitor, MLN4924, as demonsrtated in FIG. 5A and FIG. 5B.
  • the binding with DDB1 also played a role in the heterobifunctional compounds ability to induce degradation of P300 and CBP proteins.
  • the D-13 mediated degradation could be partially neutralized by co-administration with excess DDB1 ligand, BL-11, that competed for DDB1 binding, as demonstrated in FIG. 5B.
  • Heterobifunctional compounds dose-dependently suppressed viability of LNCaP cells, as exemplified by D-2, or D-7 (FIG. 6) . These results demonstrated that downregulation of CBP/P300 proteins levels by using heterobifunctional compounds described herein induced antiproliferation activities. Comapred to the p300/CBP inhibitor GNE-781, the exemplified heterobifunctional p300/CBP degrader compounds D-2 and D-7 induced more potent inhibitory effects on the growth of LNCaP cells. Overall, the heterobifunctional degrader compounds described herein could be more potent for inducing cellular effects such as inhibiting cell growth or viability than target protein inhibitors.
  • Additional heterobifunctional compounds were designed and tested for their ability to target and degrade another two target proteins, CDK4 and CDK6.
  • Calu-1 cells that express CDK4/6 proteins were treated with heterobifunctional compounds disclosed herein (D-44 to D-49) at indicated concentrations for 16 hours. Cells were collected, lysed and subject to immunoblotting using an antibody specific to CDK4, CDK6 or phosphorylated Rb proteins. Tubulin was included as the loading control. DMSO treatment was used as the negative control.
  • CDK4 and CDK6 protein levels in Calu-1 cells were significantly decreased in a concentration-dependent manner, along with the decreased downstream Rb phosphorylation accordingly (FIG. 7A and FIG. 7B) .
  • FIG. 10, 11, 13 and 14 include western blots of various proteins including cyclin D1, cyclin D2, cyclin D3, CDK4, CDK6, or phospho-Rb after treatment with heterobifunctional compounds.
  • Some heterobifunctional compounds were more potent or effective than others at reducing expression of proteins shown in these figures. For example, some heterobifunctional compounds were more effective at lower doses than others.
  • These data show that heterobifunctional compounds in accordance with this disclosure may be effective at binding, inhibiting, or degrading a target protein. These compounds may be effective in multiple cell types.
  • FIG. 12 and Table 8 include cell viability data after treatment with heterobifunctional compound D-128, D129, or D-130. These heterobifunctional compounds were more potent or effective than palbociclib at reducing viability in a variety of different cell types. For example, D-128, D129, or D-130 were more effective at lower doses than palbociclib. The data show that heterobifunctional compounds in accordance with this disclosure may be effective at inhibiting cell viability. The compounds may be effective in multiple cell types.
  • Amino refers to the —NH 2 radical.
  • Niro refers to the -NO 2 radical.
  • Oxa refers to the -O-radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl) .
  • an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl) .
  • an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl) .
  • an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl) .
  • an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl) . In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl) . In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl) . In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl) . In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl) .
  • an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl) . In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl) . In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl) .
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl) , 1-methylethyl (iso-propyl) , 1-butyl (n-butyl) , 1-methylpropyl (sec-butyl) , 2-methylpropyl (iso-butyl) , 1, 1-dimethylethyl (tert-butyl) , 1-pentyl (n-pentyl) .
  • the alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, R a , -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Haloalkyl refers to an alkyl group that is substituted by one or more halogens.
  • exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2 trifluoroethyl, 1, 2 difluoroethyl, 3 bromo 2 fluoropropyl, and 1, 2 dibromoethyl.
  • Heteroalkyl refers to substituted or unsubstituted alkyl, alkenyl and alkynyl groups which respectively have one or more skeletal chain atoms selected from an atom other than carbon.
  • Exemplary skeletal chain atoms selected from an atom other than carbon include, e.g., O, N, P, Si, S, or combinations thereof, wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. If given, a numerical range refers to the chain length in total.
  • a 3-to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl) , prop-1-enyl (i.e., allyl) , but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-1-enyl i.e., allyl
  • pent-1-enyl penta-1, 4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, R a , -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) ,
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl comprises two to six carbon atoms.
  • an alkynyl comprises two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, R a , -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) ,
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene) . In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C 5 alkylene) . In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene) . In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene) . In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene) .
  • an alkylene comprises one carbon atom (e.g., C 1 alkylene) . In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene) . In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene) . In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkylene) .
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, R a , -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl” ) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a , -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OR a , -R b
  • Alkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Carbocyclyl or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms.
  • a carbocyclyl comprises five to seven carbon atoms.
  • the carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds) .
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as “cycloalkenyl.
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo [2.2.1] heptanyl) , norbornenyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a , -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OC
  • Carbocyclylalkyl refers to a radical of the formula –R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heterocyclyl or “heterocycloalkyl” refers to a stable 3-to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated.
  • heterocyclyl is attached to the rest of the molecule through any atom of the ring (s) .
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyr
  • heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a , -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OC (O)
  • N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • C-heterocyclyl or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
  • a C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-or 3-or 4-piperidinyl, 2-piperazinyl, 2-or 3-pyrrolidinyl, and the like.
  • Heteroaryl refers to a radical derived from a 3-to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom (s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring (s) .
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d] thiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, benzo [b] [1, 4] oxazinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzo
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a , -R b -OR a , -R b -OC (O) -R a , -
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R) -or (S) -. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans. ) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C-or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • isotopes such as for example, deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not,
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts, " Journal of Pharmaceutical Science, 66: 1-19 (1997) ) .
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al
  • the in vivo modified protein comprises a DNA damage-binding protein 1 (DDB1) protein.
  • DDB1 protein is bound to a ligand.
  • the ligand is a DDB1 ligand.
  • the DDB1 protein is directly bound to the ligand.
  • the binding between the DDB1 protein and the ligand is non-covalent.
  • the binding between the DDB1 protein and the ligand is covalent.
  • the ligand may be any ligand described herein.
  • the ligand comprises a DDB1 binding moiety such as a DDB1 binding moiety described herein.
  • the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety described herein.
  • a DDB1 protein is modified in vivo by being bound to a ligand administered to a subject.
  • a modified protein may include an engineered protein.
  • engineered DDB1 proteins such as an in vivo engineered DDB1 protein.
  • the engineered DDB1 protein may be bound to a ligand.
  • the engineered DDB1 protein may bind to the ligand in vivo.
  • the ligand may be administered to a subject, and bind to a DDB1 protein or engineered DDB1 protein in vivo.
  • the in vivo modified protein comprises a DDB1 protein directly bound to a ligand comprising a DDB1 binding moiety. In some embodiments, the in vivo modified protein comprises a DDB1 protein directly bound to a ligand, the ligand comprising a DDB1 binding moiety. In some embodiments, the in vivo modified protein comprises a DDB1 protein directly bound to a heterobifunctional compound, the heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the ligand comprises a DDB1 binding moiety.
  • the ligand comprises a linker.
  • the ligand comprises a target protein binding moiety.
  • the DDB1 binding moiety is covalently connected to a linker.
  • the linker is further connected to a target protein binding moiety.
  • the DDB1 binding moiety is covalently connected through a linker to a target protein binding moiety.
  • the DDB1 binding moiety is covalently connected to a target protein binding moiety without a linker.
  • target protein binding moiety binds to a target protein such as a target protein described herein.
  • the ligand comprises a compound described herein.
  • the ligand may comprise a DDB1 binding moiety disclosed herein, or the ligand may comprise a linker disclosed herein, or the ligand may comprise a target protein binding moiety disclosed herein.
  • a linker is a bond. In some embodiments, the linker is more than just a bond.
  • the ligand is a small molecule.
  • the ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the DDB1 binding moiety is bound to a binding region on the DDB1 protein.
  • the binding region on the DDB1 protein comprises a beta propeller domain.
  • the beta propeller domain comprises a beta propeller C (BPC) domain.
  • the binding region on the DDB1 protein comprises a BPC domain.
  • the binding region on the DDB1 protein comprises a top face of the BPC domain.
  • the binding region on the DDB1 protein comprises one or more of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • DDB1 residues ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU78
  • one or more of the following DDB1 residues are involved in the non-covalent binding between the DDB1 protein and the ligand: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • An in vivo engineered DDB1 protein may include a DDB1 protein bound to a ligand at any of the aforementioned residues.
  • the binding region on the DDB1 protein comprises ARG327 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises LEU328 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises PRO358 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ILE359 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises VAL360 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ASP361 of the DDB1 protein.
  • the binding region on the DDB1 protein comprises GLY380 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA381 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises PHE382 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER720 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ARG722 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises LYS723 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER738 of the DDB1 protein.
  • the binding region on the DDB1 protein comprises ILE740 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises GLU787 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises TYR812 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises LEU814 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER815 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA834 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises VAL836 of the DDB1 protein.
  • the binding region on the DDB1 protein comprises ALA841 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA869 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises TYR871 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER872 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises MET910 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises LEU912 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises TYR913 of the DDB1 protein.
  • the binding region on the DDB1 protein comprises LEU926 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises TRP953 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER955 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA956 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ASN970 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA971 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises PHE972 of the DDB1 protein.
  • the binding region on the DDB1 protein comprises PHE1003 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ASN1005 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises VAL1006 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises VAL1033 of the DDB1 protein.
  • the binding between the DDB1 protein and the ligand comprises one or more of a salt-bridge, a Coulombic interaction, a hydrogen bond, a stereoelectronic interaction, and a dispersion contact.
  • the binding between the DDB1 protein and the ligand comprises a salt-bridge.
  • the binding between the DDB1 protein and the ligand comprises a Coulombic interaction.
  • the binding between the DDB1 protein and the ligand comprises one or more hydrogen bonds.
  • the binding between the DDB1 protein and the ligand comprises a stereoelectronic interaction.
  • the binding between the DDB1 protein and the ligand comprises a dispersion contacts.
  • the DDB1 protein comprises a BPC domain comprising a central cavity. In some embodiments, the ligand binds the DDB1 protein in the central cavity of the BPC domain. In some embodiments, the DDB1 protein comprises a WD40-motiff. In some embodiments, the WD40-motiff comprises a center. In some embodiments, the ligand is anchored toward the center of the WD40-motiff. In some embodiments, the ligand is anchored toward the center of the WD40-motiff by a salt-bridge. In some embodiments, the ligand includes a nitro group.
  • the salt-bridge is between the primary amine of an amino acid of the DDB1 protein and the ligand’s nitro group. In some embodiments, the salt-bridge is between the primary amine of a lysine (e.g. LYS723) of the DDB1 protein and the ligand’s nitro group.
  • LYS723 a lysine
  • the ligand is anchored toward the center of the WD40-motiff by a Coulombic interaction.
  • the ligand includes an electron deficient nitrogen.
  • the nitro group includes an electron deficient nitrogen.
  • the Coulombic interaction is between the electron-deficient nitrogen and a lone-pair of a nearby water.
  • the nearby water is ordered between a backbone carbonyl oxygen atom of one or more amino acids of the DDB1 protein.
  • the nearby water is ordered between a backbone carbonyl oxygen atom of an arginine (e.g. ARG722) of the DDB1 protein.
  • the nearby water is ordered between a backbone carbonyl oxygen atom of a valine (e.g. VAL360) of the DDB1 protein.
  • the nearby water is ordered between the primary amine of a lysine such as LYS723.
  • the nearby water is ordered between the backbone carbonyl oxygen atom of the arginine, and the backbone carbonyl oxygen atom of the valine, and/or the primary amine of the lysine.
  • the nearby water is ordered between the backbone carbonyl oxygen atoms of ARG722 and VAL360 as well as the primary amine of LYS723.
  • the ligand is anchored toward the center of the WD40-motiff by the Coulombic interaction and the salt-bridge.
  • the ligand includes a thiazole. In some embodiments, the ligand includes an amide. In some embodiments, the ligand includes an acetate. In some embodiments, the ligand includes one or more pi-faces. In some embodiments, the ligand includes a pi-face of a thiazole. In some embodiments, the ligand includes a pi-face of an amide. In some embodiments, the pi-faces of the thiazole and the amide rest over an amino acid sidechain. In some embodiments, the pi-faces of the thiazole and the amide rest over a valine (e.g. VAL360) sidechain.
  • valine e.g. VAL360
  • the the amide forms an intermolecular hydrogen bond with a sidechain of an amino acid of the DDB1 protein. In some embodiments, the the amide forms a hydrogen bond with a sidechain of an asparginine (e.g. ASN1005) of the DDB1 protein. In some embodiments, the the amide forms an intramolecular hydrogen bond with the acetate. In some embodiments, the the amide forms an intermolecular hydrogen bond with a sidechain of the asparagine and an intramolecular hydrogen bond with the acetate. In some embodiments, the ligand includes thiophene comprising a sulfur.
  • the sulfur of the thiophene is geometrically stabilized through a stereoelectronic interaction with an amino acid sidechain of the DDB1 protein. In some embodiments, the sulfur of the thiophene is geometrically stabilized through a stereoelectronic interaction with the sidechain of the asparginine (e.g. ASN1005) .
  • the acetate comprises a methyl group that forms a dispersion contact with an ordered water. In some embodiments, the acetate comprises a methyl group that forms a dispersion contact with an amino acid sidechain of the DDB1 protein. In some embodiments, the acetate comprises a methyl group that forms a dispersion contact with an arginine (e.g.
  • the acetate comprises a methyl group that forms dispersion contacts with the arginine sidechain of the DDB1 protein and an ordered water.
  • the ligand includes a benzene ring.
  • the benzene ring forms dispersion contacts with amino acid sidechains of the DDB1 protein.
  • the benzene ring forms a dispersion contact with an alanine (e.g. ALA381) sidechain of the DDB1 protein.
  • the benzene ring forms a dispersion contact with a leucine (e.g. LEU328) sidechain of the DDB1 protein.
  • the benzene ring forms a dispersion contact with a proline (e.g. PRO358) sidechain of the DDB1 protein. In some embodiments, the benzene ring forms a dispersion contact with a valine (e.g. VAL1033) sidechain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contacts with the alanine, leucine, proline, and valine sidechains of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contacts with ALA381, LEU328, PRO358 and VAL1033 sidechains of the DDB1 protein.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) below 100 ⁇ M, a Kd below 90 ⁇ M, a Kd below 80 ⁇ M, a Kd below 70 ⁇ M, a Kd below 60 ⁇ M, below 50 ⁇ M, a Kd below 45 ⁇ M, a Kd below 40 ⁇ M, a Kd below 35 ⁇ M, a Kd below 30 ⁇ M, a Kd below 25 ⁇ M, a Kd below 20 ⁇ M, a Kd below 15 ⁇ M, a Kd below 14 ⁇ M, a Kd below 13 ⁇ M, a Kd below 12 ⁇ M, a Kd below 11 ⁇ M, a Kd below 10 ⁇ M, a Kd below 9 ⁇ M, a Kd below 8 ⁇ M, a Kd below 7 ⁇ M,
  • Kd equilibrium dissociation constant
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 uM, a Kd from 20-100 uM, or a Kd >100 uM.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity disclosed herein (e.g. a binding affinity described in the section titled, “DDB1 Binding Moieties, ” or in Table 6 or Table 7) .
  • An in vivo engineered DDB1 protein may include a DDB1 protein bound to a ligand with any of the aforementioned binding affinities.
  • the binding between the DDB1 binding moiety and the DDB1 protein is non-covalent.
  • the binding may include a non-covalent bond.
  • the binding may include more than one non-covalent bond.
  • Some non-limiting examples of non-covalent bonds include a salt-bridge, a Coulombic interaction, a hydrogen bond, a stereoelectronic interaction, or a dispersion contact.
  • the binding may include a combination of non-covalent bonds.
  • the binding between the DDB1 binding moiety and the DDB1 protein is covalent.
  • the ligand-protein complex comprises a ligand-DNA damage-binding protein 1 (DDB1) complex.
  • DDB1 ligand-DNA damage-binding protein 1
  • the ligand-DDB1 complex is formed by binding a DDB1 protein to a ligand.
  • the ligand is a DDB1 ligand.
  • the binding is directly between the DDB1 protein and the ligand.
  • the DDB1 protein is directly bound to the ligand.
  • the binding is non-covalent.
  • the binding is covalent.
  • the DDB1 is directly bound to the ligand.
  • the ligand may be any ligand described herein.
  • the ligand comprises a DDB1 binding moiety such as a DDB1 binding moiety described herein.
  • the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety described herein.
  • the ligand-DDB1 complex is formed by non-covalently binding a DDB1 protein directly to a ligand, the ligand comprising a DDB1 binding moiety. In some embodiments, the ligand-DDB1 complex is formed by covalently binding a DDB1 protein directly to a ligand, the ligand comprising a DDB1 binding moiety.
  • the ligand-DDB1 complex is formed by non-covalently binding a DDB1 protein directly to a heterobifunctional compound, the heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety. In some embodiments, the ligand-DDB1 complex is formed by covalently binding a DDB1 protein directly to a heterobifunctional compound, the heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the ligand comprises a DDB1 binding moiety.
  • the ligand comprises a linker.
  • the ligand comprises a target protein binding moiety.
  • the DDB1 binding moiety is covalently connected to a linker.
  • the linker is further connected to a target protein binding moiety.
  • the DDB1 binding moiety is covalently connected through a linker to a target protein binding moiety.
  • the DDB1 binding moiety is covalently connected to a target protein binding moiety without a linker.
  • target protein binding moiety binds to a target protein such as a target protein described herein.
  • the ligand comprises a compound described herein.
  • the ligand may comprise a DDB1 binding moiety disclosed herein, or the ligand may comprise a linker disclosed herein, or the ligand may comprise a target protein binding moiety disclosed herein.
  • the ligand is a small molecule.
  • the ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the DDB1 binding moiety is bound to a binding region on the DDB1 protein.
  • the binding region on the DDB1 protein comprises a beta propeller domain.
  • the beta propeller domain comprises a beta propeller C (BPC) domain.
  • the binding region on the DDB1 protein comprises a BPC domain.
  • the binding region on the DDB1 protein comprises a top face of the BPC domain.
  • the binding region on the DDB1 protein comprises one or more of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • one or more of the following DDB1 residues are involved in the non-covalent binding between the DDB1 protein and the ligand: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • the binding region on the DDB1 protein comprises an amino acid residue described herein, such as in the section titled “Modified Proteins. ”
  • the binding between the DDB1 protein and the ligand comprises one or more of a salt-bridge, a Coulombic interaction, a hydrogen bond, a stereoelectronic interaction, and a dispersion contact.
  • the binding between the DDB1 protein and the ligand comprises a salt-bridge.
  • the binding between the DDB1 protein and the ligand comprises a Coulombic interaction.
  • the binding between the DDB1 protein and the ligand comprises one or more hydrogen bonds.
  • the binding between the DDB1 protein and the ligand comprises a stereoelectronic interaction.
  • the binding between the DDB1 protein and the ligand comprises a dispersion contacts.
  • the DDB1 protein comprises a BPC domain comprising a central cavity. In some embodiments, the ligand binds the DDB1 protein in the central cavity of the BPC domain. In some embodiments, the DDB1 protein comprises a WD40-motiff. In some embodiments, the WD40-motiff comprises a center. In some embodiments, the ligand is anchored toward the center of the WD40-motiff. In some embodiments, the ligand is anchored toward the center of the WD40-motiff by a salt-bridge. In some embodiments, the ligand includes a nitro group.
  • the salt-bridge is between the primary amine of an amino acid of the DDB1 protein and the ligand’s nitro group. In some embodiments, the salt-bridge is between the primary amine of a lysine (e.g. LYS723) of the DDB1 protein and the ligand’s nitro group.
  • LYS723 a lysine
  • the ligand is anchored toward the center of the WD40-motiff by a Coulombic interaction.
  • the ligand includes an electron deficient nitrogen.
  • the nitro group includes an electron deficient nitrogen.
  • the Coulombic interaction is between the electron-deficient nitrogen and a lone-pair of a nearby water.
  • the nearby water is ordered between a backbone carbonyl oxygen atom of one or more amino acids of the DDB1 protein.
  • the nearby water is ordered between a backbone carbonyl oxygen atom of an arginine (e.g. ARG722) of the DDB1 protein.
  • the nearby water is ordered between a backbone carbonyl oxygen atom of a valine (e.g. VAL360) of the DDB1 protein.
  • the nearby water is ordered between the primary amine of a lysine such as LYS723.
  • the nearby water is ordered between the backbone carbonyl oxygen atom of the arginine, and the backbone carbonyl oxygen atom of the valine, and/or the primary amine of the lysine.
  • the nearby water is ordered between the backbone carbonyl oxygen atoms of ARG722 and VAL360 as well as the primary amine of LYS723.
  • the ligand is anchored toward the center of the WD40-motiff by the Coulombic interaction and the salt-bridge.
  • the ligand includes a thiazole. In some embodiments, the ligand includes an amide. In some embodiments, the ligand includes an acetate. In some embodiments, the ligand includes one or more pi-faces. In some embodiments, the ligand includes a pi-face of a thiazole. In some embodiments, the ligand includes a pi-face of an amide. In some embodiments, the pi-faces of the thiazole and the amide rest over an amino acid sidechain. In some embodiments, the pi-faces of the thiazole and the amide rest over a valine (e.g. VAL360) sidechain.
  • valine e.g. VAL360
  • the the amide forms an intermolecular hydrogen bond with a sidechain of an amino acid of the DDB1 protein. In some embodiments, the the amide forms a hydrogen bond with a sidechain of an asparginine (e.g. ASN1005) of the DDB1 protein. In some embodiments, the the amide forms an intramolecular hydrogen bond with the acetate. In some embodiments, the the amide forms an intermolecular hydrogen bond with a sidechain of the asparagine and an intramolecular hydrogen bond with the acetate. In some embodiments, the ligand includes thiophene comprising a sulfur.
  • the sulfur of the thiophene is geometrically stabilized through a stereoelectronic interaction with an amino acid sidechain of the DDB1 protein. In some embodiments, the sulfur of the thiophene is geometrically stabilized through a stereoelectronic interaction with the sidechain of the asparginine (e.g. ASN1005) .
  • the acetate comprises a methyl group that forms a dispersion contact with an ordered water. In some embodiments, the acetate comprises a methyl group that forms a dispersion contact with an amino acid sidechain of the DDB1 protein. In some embodiments, the acetate comprises a methyl group that forms a dispersion contact with an arginine (e.g.
  • the acetate comprises a methyl group that forms dispersion contacts with the arginine sidechain of the DDB1 protein and an ordered water.
  • the ligand includes a benzene ring.
  • the benzene ring forms dispersion contacts with amino acid sidechains of the DDB1 protein.
  • the benzene ring forms a dispersion contact with an alanine (e.g. ALA381) sidechain of the DDB1 protein.
  • the benzene ring forms a dispersion contact with a leucine (e.g. LEU328) sidechain of the DDB1 protein.
  • the benzene ring forms a dispersion contact with a proline (e.g. PRO358) sidechain of the DDB1 protein. In some embodiments, the benzene ring forms a dispersion contact with a valine (e.g. VAL1033) sidechain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contacts with the alanine, leucine, proline, and valine sidechains of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contacts with ALA381, LEU328, PRO358 and VAL1033 sidechains of the DDB1 protein.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) below 100 ⁇ M, a Kd below 90 ⁇ M, a Kd below 80 ⁇ M, a Kd below 70 ⁇ M, a Kd below 60 ⁇ M, a Kd below 50 ⁇ M, a Kd below 45 ⁇ M, a Kd below 40 ⁇ M, a Kd below 35 ⁇ M, a Kd below 30 ⁇ M, a Kd below 25 ⁇ M, a Kd below 20 ⁇ M, a Kd below 15 ⁇ M, a Kd below 14 ⁇ M, a Kd below 13 ⁇ M, a Kd below 12 ⁇ M, a Kd below 11 ⁇ M, a Kd below 10 ⁇ M, a Kd below 9 ⁇ M, a Kd below 8 ⁇ M, a Kd
  • Kd equilibrium dissociation constant
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 uM, a Kd from 20-100 uM, or a Kd > 100 uM.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity disclosed herein (e.g. a binding affinity described in the section titled, “DDB1 Binding Moieties, ” or in Table 6 or Table 7) .
  • ligand-protein complexes are ligand-protein complexes.
  • the binding between the DDB1 binding moiety and the DDB1 protein is non-covalent.
  • the binding between the DDB1 binding moiety and the DDB1 protein is covalent.
  • ligand-protein complexes are ligand-protein complexes.
  • the complex is formed in vivo. In some embodiments, the complex is formed in vitro.
  • the compound may be or include a DDB1 ligand.
  • the compound may comprise a DDB1 binding moiety.
  • the compound may comprise a linker.
  • the compound may comprise a target protein binding moiety.
  • the ligand may be a heterobifunctional compound.
  • the heterobifunctional compound may comprise a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the compound may comprise a ligand.
  • the ligand may comprise a DDB1 binding moiety.
  • the ligand may comprise a linker.
  • the ligand may comprise a target protein binding moiety.
  • the DDB1 binding moiety may be connected via the linker to the target protein binding moiety.
  • the ligand may be a heterobifunctional compound.
  • the heterobifunctional compound may comprise a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • the ligand may include a small molecule.
  • An example of a small molecule is an organic compound having a molecular weight of less than 900 daltons.
  • the ligand may have a molecular weight below 2500 daltons, below 2250 daltons, below 2000 daltons, below 1750 daltons, below 1500 daltons, or below 1250 daltons.
  • the ligand may have a molecular weight below 1000 daltons, below 900 daltons, below 800 daltons, below 700 daltons, below 600 daltons, or below 500 daltons.
  • the ligand may have a molecular weight greater than 2500 daltons, greater than 2250 daltons, greater than 2000 daltons, greater than 1750 daltons, greater than 1500 daltons, or greater than 1250 daltons.
  • the ligand may have a molecular weight greater than 1000 daltons, greater than 900 daltons, greater than 800 daltons, greater than 700 daltons, greater than 600 daltons, or greater than 500 daltons.
  • ⁇ are compounds for use in a method such as a method of treatment. Some embodiments include a compound for use in a method of degrading, inhibiting, or modulating a protein or a target protein. The compound may be or include a compound described herein. Some embodiments include a method of making a compound disclosed herein.
  • Described herein are compounds comprising a DDB1 binding moiety. Some such compounds may be useful as an antiviral drug, as a DDB1 protein level or function modulator, as part of a molecular glue, or as part of a targeted protein degrader. In some embodiments, the DDB1 binding moiety is included as part of a heterobifunctional compound.
  • the DDB1 binding moiety binds to a DDB1 protein.
  • the DDB1 binding moiety is bound to a DDB1 protein.
  • the compound binds to a DDB1 protein via the DDB1 binding moiety.
  • the compound is bound to a DDB1 protein via the DDB1 binding moiety.
  • a compound of Formula (I) comprises a structure of any one of Formula (II) , Formula (IIa) , or Formula (IIb) .
  • the compound or the DDB1 binding moiety does not inhibit DDB1 function.
  • binding of DDB1 to the DDB1 binding moiety may, in some embodiments, not prevent or reduce associations between DDB1 and a cullin protein such as Cullin 4A or Cullin 4B.
  • a DDB1 binding moiety is a small molecule.
  • a DDB1 binding moiety described herein comprises the structure of Formula (II) :
  • F 1 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5.
  • F 1 is aryl. In some embodiments of a compound of Formula (II) , F 1 is heteroaryl. In some embodiments of a compound of Formula (II) , F 1 is 5-12 membered heteroaryl. In some embodiments of a compound of Formula (II) , F 1 is phenyl. In some embodiments of a compound of Formula (II) , F 1 is phenyl and q is 1. In some embodiments of a compound of Formula (II) , F 2 is aryl. In some embodiments of a compound of Formula (II) , F 2 is C 6 -C 12 aryl.
  • F 2 is heteroaryl. In some embodiments of a compound of Formula (II) , F 2 is 5-12 membered heteroaryl. In some embodiments of a compound of Formula (II) , F 2 is a five membered membered ring heteroaryl. In some embodiments of a compound of Formula (II) , F 2 is a six membered membered ring heteroaryl. In some embodiments of a compound of Formula (II) , F 2 is an N-heterocyclyl ring.
  • F 2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.
  • F 2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl, and q is 1.
  • F 2 is 5-6 membered heteroaryl.
  • F 2 is heteroaryl, wherein the heteroaryl group has at least one nitrogen atom in the ring. In some embodiments, F 2 is heteroaryl, wherein the heteroaryl group has at least two nitrogen atoms in the ring. In some embodiments, F 2 is pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, F 2 is heteroaryl, wherein the heteroaryl group has at least one sulfur atom in the ring. In some embodiments, F 2 is heteroaryl, wherein the heteroaryl group has at least one oxygen atom in the ring. In some embodiments, F 2 is thiazolyl, oxazolyl, furyl, or thiophenyl.
  • F 2 is thiazolyl.
  • R 12 at each occurrence, is -NO 2 , halogen, methyl, halomethyl, phenyl, cyclopropyl, SO 2 CH 3 , or -CN.
  • R 12 is -NO 2 .
  • R 12 at each occurrence, is chloro or bromo.
  • a DDB1 binding moiety comprises nitazoxanide or a pharmaceutically acceptable salt thereof.
  • a DDB1 binding moiety described herein comprises the structure of Formula (IIa) :
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5.
  • F 2 is aryl. In some embodiments of a compound of Formula (IIa) , F 2 is C 6 -C 12 aryl. In some embodiments of a compound of Formula (IIa) , F 2 is heteroaryl. In some embodiments of a compound of Formula (IIa) , F 2 is 5-12 membered heteroaryl.
  • F 2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.
  • F 2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl, and p is 1.
  • F 2 is 5-6 membered heteroaryl. In some embodiments of a compound of Formula (IIa) F 2 is heteroaryl, wherein the heteroaryl group has at least one nitrogen atom in the ring. In some embodiments of a compound of Formula (IIa) F 2 is heteroaryl, wherein the heteroaryl group has at least two nitrogen atoms in the ring. In some embodiments of a compound of Formula (IIa) F 2 is pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, F 2 is heteroaryl, wherein the heteroaryl group has at least one sulfur atom in the ring.
  • F 2 is heteroaryl, wherein the heteroaryl group has at least one oxygen atom in the ring.
  • F 2 is thiazolyl, oxazolyl, furyl, or thiophenyl.
  • F 2 is thiazolyl.
  • R 12 at each occurrence, is -NO 2 , halogen, methyl, halomethyl, phenyl, cyclopropyl, SO 2 CH 3 , or -CN.
  • R 12 is -NO 2 .
  • R 12 at each occurrence, is chloro or bromo.
  • q is 1. In some embodiments of a compound of Formula (IIa) , q is 2.
  • a compound described herein comprises the structure of Formula (IIb) :
  • a 4 and A 5 are each independently S, N, or O, wherein at least one of A 4 or A 5 is N;
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-3.
  • the DDB1 binding moiety is incorporated into a ligand described herein. In some embodiments, the DDB1 binding moiety is part of a modified protein described herein. In some embodiments, the DDB1 binding moiety is part of a ligand-protein complex described herein. In some embodiments, the DDB1 binding moiety is attached to a linker such as a linker described herein. In some embodiments, the DDB1 binding moiety is covalently connected through the linker to a target protein binding moiety described herein.
  • Described herein are compounds comprising a DDB1 binding moiety.
  • the DDB1 binding moiety comprises a compound of Table 1.
  • a compound of Table 1 is capped with a capping group to simulate a linker.
  • capping group comprises a substituted amino group.
  • a capping group comprises an N-alkyl or N-dialkyl group, an acetamide, an alkyl or haloalkyl group, a lactam, an aminofuran, or an aminopyran group.
  • capping groups are used to approximate the effect on activity from a similar linker.
  • a DDB1 binding moiety comprising the structure in some embodiments is incorporated into a compound comprising wherein the wavy line indicates a point of attachment to a target protein binding moiety and/or linker.
  • a DDB1 binding moiety comprising the structure in some embodiments is incorporated into a compound comprising wherein the wavy line indicates a point of attachment to a target protein binding moiety and/or linker.
  • ligands comprising a DDB1 binding moiety that binds or is bound to a DDB1 protein.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) below 100 ⁇ M, a Kd below 90 ⁇ M, a Kd below 80 ⁇ M, a Kd below 70 ⁇ M, a Kd below 60 ⁇ M, below 50 ⁇ M, a Kd below 45 ⁇ M, a Kd below 40 ⁇ M, a Kd below 35 ⁇ M, a Kd below 30 ⁇ M, a Kd below 25 ⁇ M, a Kd below 20 ⁇ M, a Kd below 15 ⁇ M, a Kd below 14 ⁇ M, a Kd below 13 ⁇ M, a Kd below 12 ⁇ M, a Kd below 11 ⁇ M, a Kd below 10 ⁇ M, a Kd below 9 ⁇
  • Kd equilibrium dissociation constant
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd value of about 100 ⁇ M, about 90 ⁇ M, about 80 ⁇ M, about 70 ⁇ M, about 60 ⁇ M, about 50 ⁇ M, about 45 ⁇ M, about 40 ⁇ M, about 35 ⁇ M, about 30 ⁇ M, about 25 ⁇ M, about 20 ⁇ M, about 15 ⁇ M, about 14 ⁇ M, about 13 ⁇ M, about 12 ⁇ M, about 11 ⁇ M, about 10 ⁇ M, about 9 ⁇ M, about 8 ⁇ M, about 7 ⁇ M, about 6 ⁇ M, about 5 ⁇ M, about 4 ⁇ M, about 3 ⁇ M, about 2 ⁇ M, or about 1 ⁇ M, or a range of Kd values defined by any two of the aforementioned Kd values.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd value of 100 ⁇ M, 90 ⁇ M, 80 ⁇ M, 70 ⁇ M, 60 ⁇ M, 50 ⁇ M, 45 ⁇ M, 40 ⁇ M, 35 ⁇ M, 30 ⁇ M, 25 ⁇ M, 20 ⁇ M, 15 ⁇ M, 14 ⁇ M, 13 ⁇ M, 12 ⁇ M, 11 ⁇ M, 10 ⁇ M, 9 ⁇ M, 8 ⁇ M, 7 ⁇ M, 6 ⁇ M, 5 ⁇ M, 4 ⁇ M, 3 ⁇ M, 2 ⁇ M, or 1 ⁇ M, or a range of Kd values defined by any two of the aforementioned Kd values.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 100 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 90 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 80 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 70 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 60 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 50 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 45 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 40 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 35 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 30 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 25 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 20 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 15 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 14 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 13 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 12 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 11 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 10 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 9 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 8 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 7 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 6 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 5 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 4 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 3 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 2 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd below 1 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 100 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 90 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 80 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 70 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 60 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 50 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 45 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 40 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 35 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 30 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 25 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 20 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 15 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 14 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 13 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 12 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 11 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 10 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 9 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 8 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 7 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 6 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 5 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 4 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 3 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 2 ⁇ M. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd above 1 ⁇ M.
  • the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 uM, a Kd from 20-100 uM, or a Kd > 100 uM. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 uM. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd from 20-100 uM. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd > 100 uM.
  • the ligand comprises a compound in Table 6, or a derivative or salt thereof.
  • the compound may include a peptide or non-peptide compound.
  • the ligand in Table 6 has category A binding, as defined in the table.
  • the ligand in Table 6 has category B binding, as defined in the table.
  • the ligand in Table 6 has category C binding, as defined in the table.
  • the ligand comprises a compound in Table 7, or a derivative or salt thereof.
  • the ligand in Table 7 has category A binding, as defined in the table.
  • the ligand in Table 7 has category B binding, as defined in the table.
  • the binding between the DDB1 binding moiety and DDB1 is non-covalent. In some embodiments, the binding between the DDB1 binding moiety and DDB1 is covalent.
  • the linker may include any linker described herein.
  • the compound is bound to DDB1 via the DDB1 binding moiety.
  • a linker is a bond.
  • a linker is not a bond (e.g. more than just a bond) .
  • a DDB1 binding moiety comprises a peptide. In some embodiments, a DDB1 binding moiety comprises no more than 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, or no more than 8 amino acids. In some embodiments, a DDB1 binding moiety comprises at least 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, or at least 8 amino acids. In some embodiments, a DDB1 binding moiety comprises about 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, or about 8 amino acids. In some embodiments, a DDB1 binding moiety comprises 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, or 8 amino acids, or a range defined by any two of the aforementioned numbers of amino acids.
  • a DDB1 binding moiety comprises a peptide derived from a virus. In some embodiments, a DDB1 binding moiety comprises a peptide of Table 3. In some embodiments, a DDB1 binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 1-7 (e.g. SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7) . In some embodiments, the DDB1 binding moiety comprises the amino acid sequence of SEQ ID NO: 1, or a variant thereof. In some embodiments, the DDB1 binding moiety comprises the amino acid sequence of SEQ ID NO: 2, or a variant thereof.
  • the DDB1 binding moiety comprises the amino acid sequence of SEQ ID NO: 3, or a variant thereof. In some embodiments, the DDB1 binding moiety comprises the amino acid sequence of SEQ ID NO: 4, or a variant thereof. In some embodiments, the DDB1 binding moiety comprises the amino acid sequence of SEQ ID NO: 5, or a variant thereof. In some embodiments, the DDB1 binding moiety comprises the amino acid sequence of SEQ ID NO: 6, or a variant thereof. In some embodiments, the DDB1 binding moiety comprises the amino acid sequence of SEQ ID NO: 7, or a variant thereof. In some embodiments, a DDB1 binding moiety has at least 99%sequence identity to any one of SEQ ID NOs: 1-7.
  • a DDB1 binding moiety has at least 98%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 97%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 96%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 95%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 94%sequence identity to any one of SEQ ID NOs: 1-7.
  • a DDB1 binding moiety has at least 93%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 92%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 91%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 90%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 89%sequence identity to any one of SEQ ID NOs: 1-7.
  • a DDB1 binding moiety has at least 88%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 87%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 86%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 85%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 80%sequence identity to any one of SEQ ID NOs: 1-7.
  • a DDB1 binding moiety has at least 75%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 70%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety has at least 65%sequence identity to any one of SEQ ID NOs: 1-7. In some embodiments, a DDB1 binding moiety comprises a variant of any one of SEQ ID NOs: 1-7, wherein at least one residue has been modified. In some embodiments, modification comprises insertion, deletion, or substitution. In some embodiments, a DDB1 binding moiety comprises a variant of any one of SEQ ID NOs: 1-7, wherein the peptide comprises at least one non-canonical amino acid.
  • Peptides may comprise non-canonical amino acids (e.g. an amino acids other than the 20 canonical amino acids normally encoded by triplet codons) .
  • a non-canonical amino acid has an (S) configuration at the alpha position.
  • a non-canonical amino acid has an (R) configuration at the alpha position.
  • a non-canonical amino acid is an alpha amino acid.
  • a non-canonical amino acid is a beta or gamma amino acid.
  • a non-canonical amino acid is selected from the group consisting of: an aromatic side chain amino acid; a non-aromatic side chain amino acid; an aliphatic side chain amino acid; a side chain amide amino acid; a side chain ester amino acid; a heteroaromatic side chain amino acid; a side chain thiol amino acid; a beta amino acid; and a backbone-modified amino acid.
  • a non-canonical amino acid is a derivative of tyrosine, histidine, tryptophan, or phenylalanine.
  • a derivative of an amino acid comprises an ester, amide, disulfide, carbamate, urea, phosphate, ether of the amino acid.
  • a non-aromatic side chain amino acid is a derivative of serine, threonine, cysteine, methionine, arginine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, proline, glycine, alanine, valine, isoleucine, or leucine.
  • a non-canonical amino acid is selected from the group consisting of 2-aminoadipic acid; 3-aminoadipic acid; beta-alanine; beta-aminoproprionic acid; 2-aminobutyric acid; 4-aminobutyric acid; piperidinic acid; 6-aminocaproic acid; 2-aminoheptanoic acid; 2-aminoisobutyric acid; 3-aminoisobutyric acid; 2-aminopimelic acid; 2, 4-diaminobutyric acid; desmosine; 2, 2'-diaminopimelic acid; 2, 3-diaminoproprionic acid; N-ethylglycine; N-ethylasparagine; hydroxylysine; allo-hydroxylysine; 3-hydroxyproline; 4-hydroxyproline; isodesmosine; allo-isoleucine; N-methylglycine; sarcosine; n-methylisoleucine; 6-N-methylly
  • a non-canonical amino acid is a proline derivative.
  • a proline derivative is 3-fluoroproline, 4-fluoroproline, 3-hydroxyproline, 4-hydroxyproline, 3-aminoproline, 4-aminoproline, 3, 4-dehydroproline, aziridine-2-carboxylic acid, azetidine-2-carboxylic acid, pipecolic acid, 4-oxa-proline, 3-thiaproline, or 4-thiaproline.
  • a non-canonical amino acid comprises a lipid.
  • Peptides may comprise modifications to the N terminus amino group (N-terminal modifications) , C terminus acid group (C-terminal modifications) , or both.
  • an unmodified N terminus comprises hydrogen.
  • an unmodified C terminus comprises a -OH.
  • an N-terminal modification comprises C 1 -C 6 acyl, C 1 -C 8 alkyl, C 6 -C 12 aralkyl, C 5 -C 10 aryl, C 4 -C 8 heteroaryl, formyl, or a lipid.
  • an N-terminal modification comprises C 6 -C 12 aralkyl.
  • an N-terminal modification comprises C 1 -C 6 acyl. In some embodiments, an N-terminal modification comprises acetyl. In some embodiments, an N-terminal modification comprises methyl, ethyl, propyl, or tert-butyl. In some embodiments, an N-terminal modification comprises benzyl. In some embodiments, an N-terminal modification comprises formyl. In some embodiments, an N-terminal modification comprises a lipid. In some embodiments, a C-terminal modification comprises an amino group, wherein the amino group is optionally substituted. In some embodiments, a C-terminal modification comprises an amino group, wherein the amino group is unsubstituted (-NH 2 ) .
  • a C-terminal modification comprises an amino group, wherein the amino group is substituted.
  • a C-terminal modification comprises -NH 2 , -amino-acyl, -amino-C 1 -C 8 alkyl, -amino-C 6 -C 12 -aralkyl, -amino-C 5 -C 10 aryl, or -amino-C 4 -C 8 heteroaryl, -amino-C 4 -C 8 heteroaryl, or -O- (C 1 -C 8 alkyl) .
  • a C-terminal modification comprises -amino-C 6 -C 12 -aralkyl.
  • a C-terminal modification comprises -O- (C 1 -C 8 alkyl) . In some embodiments, a C-terminal modification comprises -amino-C 6 -C 12 -aralkyl. In some embodiments, a C-terminal modification comprises –NH-CH 2 Ph. In some embodiments, a C-terminal modification comprises –OEt. In some embodiments, a C-terminal modification comprises –OMe.
  • Peptides may comprise lipids. Such lipids are covalently attached to an amino acid in the peptide.
  • a lipid is attached to the N-terminus.
  • a lipid is attached to cysteine, serine, lysine, threonine or tyrosine.
  • a lipid is attached to cysteine, lysine.
  • a lipid is attached to a non-canonical amino acid.
  • a lipid comprises a hydrophobic group.
  • a lipid comprises a fatty acid group.
  • a lipid comprises a C 6 -C 20 fatty acid group. In some embodiments, a lipid comprises a steroid. In some embodiments, a lipid comprises a wax. In some embodiments, a lipid comprises an alkyl group. In some embodiments, a lipid comprises a C 6 -C 20 alkyl group. In some embodiments, a lipid comprises a C 6 -C 20 alkenyl group. In some embodiments, a lipid comprises a C 6 -C 20 alkyl, C 6 -C 20 alkenyl, C 6 -C 20 alkynyl, or C 6 -C 20 acyl group.
  • a lipid comprises a geranyl, farnesyl, or geranylgeranyl group. In some embodiments, a lipid comprises a undecyloyl, lauroyl, tridecyloyl, myristoyl, palmitoyl, or stearoyl group. In some embodiments, a lipid is attached to a cysteine through palmitoylation or prenylation. In some embodiments, a peptide described herein comprises an ester, amide, or thioester of a fatty acid.
  • DDB1 binding moieties binds to a DDB1 protein. In some embodiments, the DDB1 binding moiety binds to a binding region on the DDB1 protein. In some embodiments, the DDB1 binding moiety is bound to a DDB1 protein. In some embodiments, the DDB1 binding moiety is bound to a binding region on the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises a beta propeller domain. In some embodiments, the binding region on the DDB1 protein comprises a beta propeller C (BPC) domain. In some embodiments, the binding region on the DDB1 protein comprises a top face of the BPC domain.
  • BPC beta propeller C
  • the binding region on the DDB1 protein comprises one or more of the following DDB1 protein residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, and/or VAL1033.
  • DDB1 protein residues ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740
  • one or more of the following DDB1 protein residues are involved in the non-covalent binding between the DDB1 protein and the ligand: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, and/or VAL1033.
  • the binding region on the DDB1 protein comprises an amino acid residue described herein, such as in the section titled “Modified Proteins. ”
  • the linker is connected to a DDB1 binding moiety described herein.
  • the linker is connected to a target protein binding moiety described herein.
  • the linker is connected to a DDB1 binding moiety and to a target protein binding moiety.
  • the connection is covalent.
  • the linker is incorporated into a ligand described herein.
  • a compound described herein of Formula (I) comprises a linker of Formula (III) , Formula (IIIa) , Formula (IIIb) ,
  • the linker comprises optionally substituted polyethylene glycol (PEG) .
  • the linker comprises an optionally substituted alkyl chain.
  • the linker is a straight chain alkane.
  • the linker comprises optionally substituted C 2 -C 30 , C 2 -C 25 , C 3 -C 25 , C 4 -C 10 , C 6 -C 12 , C 6 -C 18 , or C 4 -C 20 alkyl units
  • the linker comprises an optionally substituted carbocycle ring.
  • the linker comprises an optionally substituted heterocycle ring. In some embodiments, the linker comprises an optionally substituted aryl ring. In some embodiments, the linker comprises an optionally substituted hetroaryl ring. In some embodiments, the linker comprises ethers. In some embodiments, the linker is comprises a C 2 -C 30 , C 2 -C 25 , C 3 -C 25 , C 4 -C 10 , C 6 -C 12 , C 6 -C 18 , or C 4 -C 20 alkylether units.
  • the PEG is optionally substituted 1-5, 2-7, 2-10, 2-20, 5-25, or 4-30 - (O-CH 2 CH 2 ) -units in length.
  • the linker comprises amines.
  • the linker is comprises a C 2 -C 30 , C 2 -C 25 , C 3 -C 25 , C 4 -C 10 , C 6 -C 12 , C 6 -C 18 , or C 4 -C 20 alkylamino units.
  • the linker comprises optionally substituted 1-5, 2-7, 2-10, 2-20, 5-25, or 4-30 - (NH-CH 2 CH 2 ) -units.
  • the linker comprises amides. In some embodiments, the linker comprises sulfonamides. In some embodiments, the linker comprises carbamides. In some embodiments, the linker comprises carbamates. In some embodiments, the linker comprises carbonates. In some embodiments, a compound comprises a DDB1 binding moiety, a linker, and/or a target protein binding moiety. In some embodiments, the linker is of Formula (III) :
  • A, W, and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R’-R”, R’COR”, R’CO 2 R”, R’C (O) N (R 1 ) R”, R’C (S) N (R 1 ) R”, R’OR”, R’OC (O) R”, R’OC (O) OR”, R’OCON (R 1 ) R”, R’SR”, R’SOR”, R’SO 2 R”, R’SO 2 N (R 1 ) R”, R’N (R 1 ) R”, R’N (R 1 ) COR”, R’N (R 1 ) C (O) OR”, R’N (R 1 ) CON (R 2 ) R”, R’N (R 1 ) C (S) R”, R’N (R 1 ) S (O) R”, R’N (R 1 ) S (O) 2 R”, R’N (R 1 ) S (O) 2 N (R 2 ) R”, optionally substituted C 1 -C 8 al
  • R’ and R are independently selected from null, optionally substituted (C 1 -C 8 alkylene) -R r (preferably, CH 2 -R r ) , optionally substituted R r - (C 1 -C 8 alkylene) , optionally substituted (C 1 -C 8 alkylene) -R r - (C 1 -C 8 alkyl) , or a bivalent moiety comprising of optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 heteroalkenylene, optionally substituted C 2 -C 8 heteroalkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8
  • R r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 4 -C 13 fused carbocyclyl, optionally substituted C 5 -C 13 fused heterocyclyl, optionally substituted C 5 -C 13 bridged carbocyclyl, optionally substituted C 5 -C 13 bridged heterocyclyl, optionally substituted C 5 -C 13 spiro carbocyclyl, optionally substituted C 5 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 hetroalkenyl, optionally substituted C 2 -C 8 hetroalkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or
  • R’ and R together with the atom to which they are connected optionally form a 3-20 membered carbocyclyl or 4-20 membered heterocyclyl ring;
  • m 0 to 15.
  • linker of Formula (III) A is (CH 2 ) 0-12 N (R 1 ) , B is null, and W is alkylene. In some embodiments of linker of Formula (III) , A is (CH 2 ) 0-12 OC (O) , B is null, and W is alkylene. In some embodiments of linker of Formula (III) , A is (CH 2 ) 0-12 N (R 1 ) C (O) , B is null, and W is alkylene. In some embodiments of linker of Formula (III) , A is (CH 2 ) 0-12 C (O) O, B is null, and W is alkylene.
  • linker of Formula (III) A is (CH 2 ) 0-12 C (O) N (R 1 ) , B is null, and W is alkylene.
  • m is 2-10.
  • m is 2-7.
  • m is 5-10.
  • linker of Formula (III) A is (CH 2 ) 0-12 N (R 1 ) , B is O, and W is alkylene. In some embodiments of linker of Formula (III) , A is (CH 2 ) 0-12 OC (O) , B is O, and W is alkylene. In some embodiments of linker of Formula (III) , A is (CH 2 ) 0-12 N (R 1 ) C (O) , B is O, and W is alkylene. In some embodiments of linker of Formula (III) , A is (CH 2 ) 0-12 C (O) O, B is O, and W is alkylene.
  • linker of Formula (III) A is (CH 2 ) 0-12 C (O) N (R 1 ) , B is O, and W is alkylene.
  • m is 2-12.
  • m is 2-7.
  • m is 5-12.
  • A is (CH 2 ) 0-12 N (R 1 )
  • B is N (R 2 )
  • W is alkylene.
  • A is (CH 2 ) 0-12 OC (O)
  • B is N (R 2 )
  • W is alkylene.
  • A is (CH 2 ) 0-12 N (R 1 ) C (O)
  • B is N (R 2 )
  • W is alkylene.
  • linker of Formula (III) A is (CH 2 ) 0-12 C (O) O, B is N (R 2 ) , and W is alkylene. In some embodiments of linker of Formula (III) , A is (CH 2 ) 0-12 C (O) N (R 1 ) , B is N (R 2 ) , and W is alkylene. In some embodiments of linker of Formula (III) , m is 2-12. In some embodiments of linker of Formula (III) , m is 2-7. In some embodiments of linker of Formula (III) , m is 5-12.
  • the linker is of Formula (IIIa) :
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 hetroalkenyl, optionally substituted C 2 -C 8 hetroalkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, and optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered
  • R 1 and R 2 , R 3 and R 4 together with the atom to which they are connected optionally form a 3-20 membered carbocyclyl or 4-20 membered heterocyclyl ring;
  • A, W, and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R’-R”, R’COR”, R’CO 2 R”, R’C (O) N (R 5 ) R”, R’C (S) N (R 5 ) R”, R’OR”, R’OC (O) R”, R’OC (O) OR”, R’OCON (R 5 ) R”, R’SR”, R’SOR”, R’SO 2 R”, R’SO 2 N (R 5 ) R”, R’N (R 5 ) R”, R’N (R 5 ) COR”, R’N (R 5 ) C (O) OR”, R’N (R 5 ) CON (R 6 ) R”, R’N (R 5 ) C (S) R”, R’N (R 5 ) S (O) R”, R’N (R 5 ) S (O) 2 R”, R’N (R 5 ) S (O) 2 N (R 6 ) R”, optionally substituted C 1 -C 8 al
  • R’ and R are independently selected from null, optionally substituted (C 1 -C 8 alkylene) -R r (preferably, CH 2 -R r ) , optionally substituted R r - (C 1 -C 8 alkylene) , optionally substituted (C 1 -C 8 alkylene) -R r - (C 1 -C 8 alkylene) , or a bivalent moiety comprising of optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 heteroalkenylene, optionally substituted C 2 -C 8 heteroalkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8
  • R r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 4 -C 13 fused carbocyclyl, optionally substituted C 5 -C 13 fused heterocyclyl, optionally substituted C 5 -C 13 bridged carbocyclyl, optionally substituted C 5 -C 13 bridged heterocyclyl, optionally substituted C 5 -C 13 spiro carbocyclyl, optionally substituted C 5 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 5 and R 6 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 hetroalkenyl, optionally substituted C 2 -C 8 hetroalkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or
  • R’ and R together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • n 0 to 15;
  • n at each occurrence, is 0 to 15;
  • o 0 to 15.
  • the linker is of Formula (IIIb) :
  • R 1 and R 2 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 hetroalkenyl, optionally substituted C 2 -C 8 hetroalkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl,
  • R 1 and R 2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • a and B are independently selected from null, or bivalent moiety selected from R’-R”, R’COR”, R’CO 2 R”, R’C (O) N (R 3 ) R”, R’C (S) N (R 3 ) R”, R’OR”, R’OC (O) R”, R’OC (O) OR”, R’OCON (R 3 ) R”, R’SR”, R’SOR”, R’SO 2 R”, R’SO 2 NR”R 3 , R’N (R 3 ) R”, R’N (R 3 ) COR”, R’N (R 3 ) C (O) OR”, R’N (R 3 ) CON (R 4 ) R”, R’N (R 3 ) C (S) R”, R’N (R 3 ) S (O) R”, R’N (R 3 ) S (O) 2 R”, R’N (R 3 ) S (O) 2 N (R 4 ) R”, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1
  • R’ and R are independently selected from null, optionally substituted (C 1 -C 8 alkylene) -R r (preferably, CH 2 -R r ) , optionally substituted R r - (C 1 -C 8 alkylene) , optionally substituted (C 1 -C 8 alkylene) -R r - (C 1 -C 8 alkylene) , or a bivalent moiety comprising of optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 heteroalkenylene, optionally substituted C 2 -C 8 heteroalkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 - C 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8
  • R L r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 4 -C 13 fused carbocyclyl, optionally substituted C 5 -C 13 fused heterocyclyl, optionally substituted C 5 -C 13 bridged carbocyclyl, optionally substituted C 5 -C 13 bridged heterocyclyl, optionally substituted C 5 -C 13 spiro carbocyclyl, optionally substituted C 5 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 3 and R 4 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 hetroalkenyl, optionally substituted C 2 -C 8 hetroalkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or
  • R’ and R together with the atom to which they are connected optionally form a 3-20 membered carbocyclyl or 4-20 membered heterocyclyl ring;
  • each m is 0 to 15;
  • n 0 to 15.
  • the linker is of Formula (IIIc) :
  • X at each occurrence, is selected from O, NH, and NR 7 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 hetroalkenyl, optionally substituted C 2 -C 8 hetroalkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylaminoC 1 -
  • a and B are independently selected from null, or bivalent moiety selected from R’-R”, R’COR”, R’CO 2 R”, R’C (O) N (R 8 ) R”, R’C (S) N (R 8 ) R”, R’OR”, R’OC (O) R”, R’OC (O) OR”, R’OCON (R 8 ) R”, R’SR”, R’SOR”, R’SO 2 R”, R’SO 2 N (R 8 ) R”, R’N (R 8 ) R”, R’N (R 8 ) COR”, R’N (R 8 ) C (O) OR”, R’N (R 8 ) CON (R 9 ) R”, R’N (R 8 ) C (S) R”, R’N (R 8 ) S (O) R”, R’N (R 8 ) S (O) 2 R”, R’N (R 8 ) S (O) 2 N (R 9 ) R”, optionally substituted C 1 -C 8 alkylene, optionally substituted C 2
  • R’ and R are independently selected from null, optionally substituted (C 1 -C 8 alkylene) -R r (preferably, CH 2 -R r ) , optionally substituted R r - (C 1 -C 8 alkylene) , or a bivalent moiety comprising of optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 heteroalkenylene, optionally substituted C 2 -C 8 heteroalkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalky
  • R r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 4 -C 13 fused carbocyclyl, optionally substituted C 5 -C 13 fused heterocyclyl, optionally substituted C 5 -C 13 bridged carbocyclyl, optionally substituted C 5 -C 13 bridged heterocyclyl, optionally substituted C 5 -C 13 spiro carbocyclyl, optionally substituted C 5 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 7 , R 8 and R 9 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 hetroalkenyl, optionally substituted C 2 -C 8 hetroalkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or
  • n 0 to 15;
  • n at each occurrence, is 0 to 15;
  • o 0 to 15;
  • p 0 to 15.
  • the linker is of Formula (IIId) :
  • A, W 1 , W 2 , and B, at each occurrence, are bivalent moieties independently selected from the group consisting of null, R’-R”, R’COR”, R’C (O) OR”, R’C (O) N (R 1 ) R”, R’C (S) N (R 1 ) R”, R’OR”, R’SR”, R’SOR”, R’SO 2 R”, R’SO 2 N (R 1 ) R”, R’N (R 1 ) R”, R’N (R 1 ) COR”, R’N (R 1 ) CON (R 2 ) R”, R’N (R 1 ) C (S) R”, optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 heteroalkenylene, optionally substituted C 2 -C 8 heteroalkyny
  • R’ and R are independently selected from null, R r , optionally substituted (C 1 -C 8 alkylene) -R r (preferably, CH 2 -R r ) , optionally substituted R r - (C 1 -C 8 alkylene) , optionally substituted (C 1 -C 8 alkylene) -R r - (C 1 -C 8 alkylene) , or a bivalent moiety comprising of optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 heteroalkenylene, optionally substituted C 2 -C 8 heteroalkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene,
  • R r at each occurrence, is selected from optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R’ and R together with the atom (s) to which they are connected optionally form a C 3 -C 20 carbocyclyl or 3-20 membered heterocyclyl ring;
  • m 0 to 15.
  • a and B are independently selected from null, CO, NH, NH-CO, CO-NH, CH 2 -NH-CO, CH 2 -CO-NH, NH-CO-CH 2 , CO-NH-CH 2 , CH 2 -NH-CH 2 -CO-NH, CH 2 -NH-CH 2 -NH-CO, -CO-NH, CO-NH-CH 2 -NH-CH 2 , CH 2 -NH-CH 2 .
  • o is 0 to 5.
  • the linker comprises a ring selected from the group consisting of a 3 to 13 membered ring, a 3 to 13 membered fused ring, a 3 to 13 membered bridged ring, and a 3 to 13 membered spiro ring.
  • the linker comprises one or more rings selected from the group consisting of Formula (IIIC1a) , Formula (IIIC2a) , Formula (IIIC3a) , Formula (IIIC4a) and Formula (IIIC5a)
  • X’ and Y’ are independently selected from N, CR b ;
  • a 1 , B 1 , C 1 and D 1 are independently selected from null, O, CO, SO, SO 2 , NR b , and CR b R c ;
  • a 2 , B 2 , C 2 , and D 2 at each occurrence, are independently selected from N, and CR b ;
  • a 3 , B 3 , C 3 , D 3 , and E 3 at each occurrence, are independently selected from N, O, S, NR b , and CR b ;
  • R b and R c are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, and optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted
  • n 1 , o 1 and p 1 are independently selected from 0, 1, 2, 3, 4 and 5.
  • the linker comprises one or more rings selected from the group consisting of Formula (IIIC1) , Formula (IIIC2) , Formula (IIIC3) , Formula (IIIC4) and Formula (IIIC5) :
  • the linker comprises one or more rings selected from:
  • a linker has the structure - (CH 2 ) 0-12 NH (CH 2 ) 2-12 NH-. In some embodiments, a linker has the structure -NH (CH 2 ) 2 NH-, -NH (CH 2 ) 3 NH-, -NH (CH 2 ) 4 NH-, -NH (CH 2 ) 5 NH-, -NH (CH 2 ) 6 NH-, -NH (CH 2 ) 7 NH-, -NH (CH 2 ) 8 NH-, -NH (CH 2 ) 9 NH-, -NH (CH 2 ) 10 NH-, -NH (CH 2 ) 11 NH-, or -NH (CH 2 ) 12 NH-.
  • a linker has the structure - (CH 2 ) 0-12 NH (CH 2 CH 2 O) 1-12 (CH 2 ) 2 NH-.
  • a linker has the structure -NH (CH 2 CH 2 O) (CH 2 ) 2 NH-, -NH (CH 2 CH 2 O) 2 (CH 2 ) 2 NH-, -NH (CH 2 CH 2 O) 3 (CH 2 ) 2 NH-, -NH (CH 2 CH 2 O) 4 (CH 2 ) 2 NH-, -NH (CH 2 CH 2 O) 5 (CH 2 ) 2 NH-, -NH (CH 2 CH 2 O) 6 (CH 2 ) 2 NH-, -NH (CH 2 CH 2 O) 7 (CH 2 ) 2 NH-, -NH (CH 2 CH 2 O) 8 (CH 2 ) 2 NH-, -NH (CH 2 CH 2 O) 9 (CH 2 ) 2 NH-, -NH (CH 2 CH 2 O) 10 (CH 2 ) 2 NH
  • a target protein comprises a transcription factor.
  • a target protein comprises an epigenetic modulator.
  • a target protein comprises p300 or CBP (CREB binding protein) .
  • a target protein comprises p300.
  • a target protein comprises CBP.
  • a target protein comprises a bromodomain-containing protein.
  • a target protein comprises bromodomain-containing protein 4 (BRD4) .
  • a target protein comprises a kinase.
  • a target protein comprises a cyclin-dependent kinase.
  • a target protein comprises a cyclin-dependent kinase (CDK) .
  • a target protein comprises cyclin-dependent kinase 4 (CDK4) or cyclin-dependent kinase 6 (CDK6) .
  • a target protein comprises CDK4.
  • a target protein comprises CDK6.
  • a target protein comprises CDK9.
  • a target protein comprises CDK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13.
  • a target protein comprises a tyrosine receptor kinase (Trk) .
  • TrkA tyrosine receptor kinase
  • TrkB tyrosine receptor kinase
  • TrkC TrkC
  • a target protein comprises mitogen-activated protein kinase kinase (MKK or MEK) .
  • MKK or MEK mitogen-activated protein kinase kinase
  • a target protein comprises MEK1.
  • a target protein comprises MEK2.
  • the heterobifunctional compound degrades the target protein.
  • target proteins include any one of B7.1, B7, TINFRlm, TNFR2, NADPH oxidase, a partner in an apoptosis pathway, BclIBax, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, a receptor, a 5HT receptor, a dopamine receptor, a G-protein (e.g.
  • Gq a histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH, a trypanosomal protein, glycogen phosphorylase, carbonic anhydrase, a chemokine receptor, JAK, STAT, RXR, RAR, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR) , protein P-glycoprotein, MRP, a tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, a Ca+ channel, VCAM, an integrin, a VLA-4 integrin, a selectin, CD40, CD40, CD
  • P2Y1, P2Y2, P2Y4, P2Y6, or P2X1-7) a farnesyltransferase, geranylgeranyl transferase, TrkA, a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, an integrin receptor, Her2 neu, telomerase inhibition, cytosolic phospholipaseA2, EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, a chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, or enolpyruvylshikimate-phosphate synthase.
  • the target protein may
  • the target protein may include a cyclin.
  • the cyclin is a cyclin D.
  • the cyclin D may include cyclin D1.
  • the cyclin D may include cyclin D2.
  • the cyclin D may include cyclin D3.
  • the heterobifunctional compound degrades the cyclin.
  • Some examples of cyclins include cyclin A, cyclin B, cyclin C, cyclin D, cyclin D1, cyclin D2, cyclin D3, cyclin E, cyclin H, cyclin K, cyclin T, or cyclin T1.
  • a target protein comprises a protein associated with a disease state.
  • the target protein may be present or upregulated in the disease state.
  • a target protein comprises a pathogen protein.
  • a target protein comprises a viral protein.
  • a target protein comprises a bacterial protein.
  • Target proteins are numerous in kind and are selected from proteins that are expressed in a cell such that at least a portion of the sequences is found in the cell and may bind to a target protein binding moiety.
  • the term “protein” may include oligopeptides and polypeptide sequences of sufficient length that they can bind to a target protein binding moiety. Any protein in a eukaryotic system or a microbial system, including a virus, bacteria or fungus, as otherwise described herein, may be a target protein for ubiquitination mediated by the compounds according to the present disclosure.
  • the target protein may be a eukaryotic protein.
  • target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism) , antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate) , receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, i
  • Proteins of interest can include proteins from eukaryotes and prokaryotes including humans as targets for drug therapy, other animals, including domesticated animals, microbials for the determination of targets for antibiotics and other antimicrobials and plants, and even viruses, among numerous others.
  • a target protein comprises any of Hsp90, a kinase, MDM2, a Human BET Bromodomain-containing protein, an HDAC, a lysine methyltransferase, an angiogenesis protein, an immunomodulatory protein, or aryl hydrocarbon receptor (AHR) .
  • a target protein comprises a heat shock protein (HSP) such as HSP90.
  • HSP heat shock protein
  • a target protein comprises a kinase or a phosphatase.
  • the target protein includes a kinase.
  • the kinase is a tyrosine kinase.
  • the kinase is VEGFR3. In some embodiments, the kinase is an aurora kinase. In some embodiments, the kinase is ALK. In some embodiments, the kinase is JAK2. In some embodiments, the kinase is Alk. In some embodiments, the kinase is Met. In some embodiments, the kinase is Abl. In some embodiments, the kinase is B-Raf or Mek. In some embodiments, a target protein comprises a phosphatase. In some embodiments, the phosphatase is a protein tyrosine phosphatase.
  • the phosphatase includes a SHP-2 domain.
  • a target protein comprises an MDM.
  • the MDM is MDM2.
  • a target protein comprises an HDAC.
  • a target protein comprises a methyltransferase such as a lysine methyltransferase.
  • a target protein comprises an angiogenesis.
  • a target protein comprises an immunomodulatory or immunosuppressive protein.
  • a target protein comprises an aryl hydrocarbon receptor (AHR) .
  • a target protein comprises RAF receptor
  • a target protein comprises FKBP.
  • the target protein comprises estrogen receptor or an androgen receptor. In some embodiments, a target protein comprises an androgen receptor. In some embodiments, a target protein comprises an estrogen receptor. In some embodiments, a target protein comprises a thyroid hormone receptor. In some embodiments, a target protein comprises an HIV protein such as an HIV protease or an HIV integrase. In some embodiments, a target protein comprises an HCV protein such as an HCV protease. In some embodiments, a target protein comprises acyl-protein thioesterase-1 or -2.
  • a ligand described herein may include a target protein binding moiety.
  • the target protein binds to or is bound by a target protein binding moiety.
  • the target protein binding moiety binds to a target protein.
  • binding of the ligand to the target protein in a cell results in degradation of the target protein.
  • the ligand may increase ubiquiting mediated target protein degradation, or proteasomal degradation of the target protein.
  • the target protein binding moiety can be any molecule that binds to a target protein.
  • the target protein binding moiety can be any small molecule known to bind to a target protein.
  • the DDB1 binding moiety binds to a DDB1 protein. In some embodiments, the DDB1 binding moiety is bound to a DDB1 protein. In some embodiments, the compound binds to a DDB1 protein via the DDB1 binding moiety. In some embodiments, the compound is bound to a DDB1 protein via the DDB1 binding moiety.
  • the DDB1 binding moiety is incorporated into a ligand described herein. In some embodiments, the DDB1 binding moiety is part of a modified protein described herein. In some embodiments, the DDB1 binding moiety is part of a ligand-protein complex described herein. In some embodiments, the DDB1 binding moiety is attached to a linker such as a linker described herein. In some embodiments, the DDB1 binding moiety is covalently connected through the linker to a target protein binding moiety described herein. In some embodiments, the target protein binding moiety is incorporated into a molecular structure or formula disclosed herein.
  • Non-limiting examples of small molecule target protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting Human BET Bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR) , among numerous others.
  • Hsp90 inhibitors kinase inhibitors
  • MDM2 inhibitors compounds targeting Human BET Bromodomain-containing proteins
  • HDAC inhibitors human lysine methyltransferase inhibitors
  • angiogenesis inhibitors angiogenesis inhibitors
  • immunosuppressive compounds and compounds targeting the aryl hydrocarbon receptor (AHR) , among numerous others.
  • AHR aryl hydrocarbon receptor
  • the protein binding moiety is a haloalkane (preferably a C1-C10 alkyl group which is substituted with at least one halo group, preferably a halo group at the distal end of the alkyl group (i.e., away from the linker or DDB1 binding moiety) , which may covalently bind to a dehalogenase enzyme in a patient or subject or in a diagnostic assay.
  • a haloalkane preferably a C1-C10 alkyl group which is substituted with at least one halo group, preferably a halo group at the distal end of the alkyl group (i.e., away from the linker or DDB1 binding moiety) , which may covalently bind to a dehalogenase enzyme in a patient or subject or in a diagnostic assay.
  • Target protein binding moieties may include any moiety which binds to a protein specifically (e.g. binds to a target protein) and may include the following non-limiting examples of small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting Human BET Bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR) , among numerous others.
  • Compositions described herein exemplify some of the members of these types of small molecule target protein binding moieties.
  • Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that may target a protein of interest. These binding moieties may be linked to a DDB1 binding moiety through a linker to present a target protein (to which the protein target moiety is bound) in proximity to the ubiquitin ligase for ubiquitination and degradation.
  • the target protein binding moiety includes a haloalkyl group, wherein said alkyl group generally ranges in size from about 1 or 2 carbons to about 12 carbons in length, often about 2 to 10 carbons in length, often about 3 carbons to about 8 carbons in length, more often about 4 carbons to about 6 carbons in length.
  • the haloalkyl groups are generally linear alkyl groups (although branched-chain alkyl groups may also be used) and are end-capped with at least one halogen group, preferably a single halogen group, often a single chloride group.
  • Haloalkyl target protein binding moieties for use in the present disclosure may be represented by the chemical structure– (CH 2 ) v-Halo where v is any integer from 2 to about 12, often about 3 to about 8, more often about 4 to about 6.
  • Halo may be any halogen, but is preferably Cl or Br, more often Cl.
  • the target protein binding moiety is a group, where w is 0 to 3, preferably 1 or 2.
  • This group may bind selectively to a target protein comprising an estrogen receptor, and may be useful for treating diseases which are modulated through estrogen receptors, and in particular cancers, such as breast cancer, endometrial cancer, ovarian cancer and uterine cancer, among others.
  • Target protein binding moieties include, for example, haloalkane halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting Human BET Bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR) .
  • Some compositions described below exemplify some of the members of these types of small molecule target protein binding moieties.
  • Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that may target a protein of interest.
  • the target protein binding moiety includes a heat shock protein (HSP; e.g. HSP90) binder or inhibitor.
  • HSP90 inhibitors as used herein include, but are not limited to: N- [4- (3H-imidazo [4, 5-C] pyridin-2-yl) -9H-fluoren-9-yl] -succinamide, 8- [ (2, 4-dimethylphenyl) sulfanyl] -3-pent-4-yn-1-yl-3H-purin-6-amine, 5- [2, 4-dihydroxy-5- (1-methylethyl) phenyl] -N-ethyl-4- [4- (morpholin-4-ylmethyl) phenyl] isoxazole-3-carboxamide, PU3, or (4E, 6Z, 8S, 9S, 10E, 12S, 13R, 14S, 16R) -13-hydroxy-8, 14, 19-trimethoxy-4, 10, 12, 16-tetramethyl-3, 20,
  • N- [4- (3H-imidazo [4, 5-C] pyridin-2-yl) -9H-fluoren-9-yl] -succinamide is attached via its terminal amide group to a linker described herein.
  • 8- [ (2, 4-dimethylphenyl) sulfanyl] -3-pent-4-yn-1-yl-3H-purin-6-amine is attached via its terminal acetylene group to a linker described herein.
  • 5- [2, 4-dihydroxy-5- (1-methylethyl) phenyl] -N-ethyl-4- [4- (morpholin-4-ylmethyl) phenyl] isoxazole-3-carboxamide is attached via its amide group (e.g. at the amine or at the alkyl group on the amine) to a linker described herein.
  • PU3 is attached via its butyl group to a linker described herein.
  • (4E, 6Z, 8S, 9S, 10E, 12S, 13R, 14S, 16R) -13-hydroxy-8, 14, 19-trimethoxy-4, 10, 12, 16-tetramethyl-3, 20, 22-trioxo-2-azabicyclo [16.3.1] or any of its derivatives are attached by an amide group to a linker described herein.
  • the target protein binding moiety includes a kinase inhibitor or a phosphatase inhibitor. In some embodiments, the target protein binding moiety includes a kinase inhibitor. In some embodiments, the kinase inhibitor is a tyrosine kinase inhibitor. In some embodiments, the kinase inhibitor is a VEGFR3 inhibitor. In some embodiments, the kinase inhibitor is an aurora kinase inhibitor. In some embodiments, the kinase inhibitor is an ALK inhibitor. In some embodiments, the kinase inhibitor is a JAK2 inhibitor. In some embodiments, the kinase inhibitor is an Alk inhibitor. In some embodiments, the kinase inhibitor is a Met inhibitor. In some embodiments, the kinase inhibitor is an Abl inhibitor. In some embodiments, the kinase inhibitor is a B-Raf/Mek inhibitor.
  • Non-limiting examples of kinase inhibitors include any one of erlotinib, sunitinib, sorafenib, desatinib, lapatinib, U09-CX-5279, Y1W, Y1X, 1-ethyl-3- (2- ⁇ [3- (1-methylethyl) [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl] sulfanyl ⁇ benzyl) urea, a 2, 6-naphthyridine, 07U, YCF, XK9, NXP, N- ⁇ 4- [ (1E) -N- (N-hydroxycarbamimidoyl) ethanehydrazonoyl] phenyl ⁇ -7-nitro-1H-indole-2-carboxamide, afatinib, fostamatinib, gefitinib, lenvatinib, vandetanib, vemura
  • erlotinib is attached via its ether group to a linker described herein.
  • sunitinib is attached via its pyrrole moiety to a linker described herein.
  • sorafenib is attached via its phenyl moiety to a linker described herein.
  • desatinib is attached via its pyrimidine to a linker described herein.
  • lapatinib is attached via its terminal methyl of its sulfonyl methyl group to a linker described herein.
  • U09-CX-5279 is attached via its amine (aniline) , carboxylic acid or amine alpha to cyclopropyl group, or cyclopropyl group to a linker described herein.
  • 1-ethyl-3- (2- ⁇ [3- (1-methylethyl) [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl] sulfanyl ⁇ benzyl) urea is attached via its propyl group to a linker described herein.
  • Y1W is attached via its propyl or butyl group to a linker described herein.
  • 6TP is attached via a terminal methyl group bound to an amide moiety to a linker described herein.
  • 07U is attached via its secondary amine or terminal amino group to a linker described herein.
  • YCF is attached via either of its terminal hydroxyl groups to a linker described herein.
  • XK9 is attached via its terminal hydroxyl group to a linker described herein.
  • NXP is attached via its terminal hydrazone group (NXP) to a linker described herein.
  • afatinib is attached via its aliphatic amine group to a linker described herein.
  • fostamatinib is attached via its methoxy group to a linker described herein.
  • gefitinib is attached via its methoxy group or its ether group to a linker described herein.
  • lenvatinib is attached via its cyclopropyl group to a linker described herein.
  • vandetanib is attached via its methoxy group or hydroxyl group to a linker described herein.
  • vemurafenib is attached via its sulfonyl propyl group to a linker described herein.
  • gleevec is attached via its amide group or via its aniline amine group to a linker described herein.
  • pazopanib is attached via its phenyl moiety or via its aniline amine group to a linker described herein.
  • AT-9283 is attached via its phenyl moiety to a linker described herein.
  • TAE684 is attached via its phenyl moiety to a linker described herein.
  • nilotinib is attached via its phenyl moiety or via its aniline amine group to a linker described herein.
  • crizotinib is attached via its phenyl moiety or diazole group to a linker described herein. In some embodiments, crizotinib is attached via its phenyl moiety or diazole group to a linker described herein. In some embodiments, JNJ FMX is attached via its phenyl moiety to a linker described herein.
  • the target protein binding moiety includes a phosphatase inhibitor.
  • the phosphatase inhibitor is a protein tyrosine phosphatase inhibitor.
  • the phosphatase inhibitor is an inhibitor of a SHP-2 domain of a tyrosine phosphatase.
  • a non-limiting example of a phosphatase inhibitors includes PTP1B.
  • Non-limiting examples of phosphatase inhibitors are included in Table 4.
  • the target protein binding moiety includes an MDM inhibitor.
  • the MDM inhibitor is an MDM2 inhibitor.
  • MDM2 inhibitors include any one of nutlin-3, nutlin-2, nutlin-1, or trans-4-iodo-4'-boranyl-chalcone.
  • nutlin-3, nutlin-2, or nutlin-1 is attached via a methoxy group or hydroxyl group to a linker described herein.
  • trans-4-iodo-4'-boranyl-chalcone is attached via its hydroxyl group to a linker described herein.
  • MDM2 inhibitors are included in Table 4.
  • the target protein binding moiety includes a compound that targets a human BET bromodomain-containing protein.
  • the compound that targets a human BET bromodomain-containing protein is a 3, 5-dimethylisoxazole.
  • Non-limiting examples of compounds that target a human BET bromodomain-containing protein are included in Table 4.
  • the target protein binding moiety includes a compound that inhibits an HDAC.
  • Non-limiting examples of compounds that inhibit an HDAC are included in Table 4.
  • the target protein binding moiety includes a compound that inhibits a methyltransferase such as a lysine methyltransferase.
  • the methyltransferase is a human lysine methyltransferase.
  • the lysine methyltransferase inhibitor is azacytidine.
  • azacytidine is attached via a hydroxy or amino group to a linker described herein.
  • the lysine methyltransferase inhibitor is decitabine.
  • decitabine is attached via a hydroxy or amino group to a linker described herein.
  • Non-limiting examples of lysine methyltransferase inhibitors are included in Table 4.
  • the target protein binding moiety includes an angiogenesis inhibitor.
  • angiogenesis inhibitors include GA-1, estradiol, testosterone, DHT, ovalicin, or fumagillin.
  • the target protein binding moiety includes an immunosuppressive compound.
  • immunosuppressive compounds include AP21998, a glucocorticoid (e.g., hydrocortisone, prednisone, prednisolone, or methylprednisolone) , beclomethasone dipropionate, methotrexate, ciclosporin, tacrolimus, rapamycin, or actinomycin.
  • the glucocorticoid is attached via a hydroxyl to a linker described herein.
  • the beclomethasone dipropionate is attached via a propionate to a linker described herein.
  • methotrexate is attached via either of its terminal hydroxyls to a linker described herein.
  • ciclosporin is attached via a butyl group to a linker described herein.
  • tacrolimus is attached via a methoxy group to a linker described herein.
  • rapamycin is attached via a methoxy group to a linker described herein.
  • actinomycin is attached via an isopropyl group to a linker described herein.
  • the target protein binding moiety includes a compound that targets an aryl hydrocarbon receptor (AHR) .
  • AHR aryl hydrocarbon receptor
  • Non-limiting examples of compounds that target an AHR include apigenin, SR1, or LGC006.
  • the target protein binding moiety includes a compound that targets a RAF receptor.
  • a compound that target a RAF receptor is included in Table 4.
  • the target protein binding moiety includes a compound that targets FKBP.
  • a compound that target FKBP is included in Table 4.
  • the target protein binding moiety includes a compound that targets an androgen receptor.
  • compounds that target an androgen receptor include any one of RU59063, SARM, DHT, MDV3100, ARN-509, a hexahydrobenzisoxazole, or a tetramethylcyclobutane.
  • Non-limiting examples of compounds that target an androgen receptor are included in Table 4.
  • the target protein binding moiety includes a compound that targets an estrogen receptor.
  • a compound that targets an estrogen receptor is included in Table 4.
  • the target protein binding moiety includes a compound that targets a thyroid hormone receptor.
  • a compound that target a thyroid hormone receptor is included in Table 4.
  • the target protein binding moiety includes a compound that inhibits an HIV protease.
  • Non-limiting examples of compounds that inhibit an HIV protease are included in Table 4.
  • the target protein binding moiety includes a compound that inhibits an HIV integrase.
  • Non-limiting examples of compounds that inhibit an HIV integrase are included in Table 4.
  • the target protein binding moiety includes a compound that targets an HCV protease.
  • a compound that targets an HCV protease is included in Table 4.
  • the target protein binding moiety includes a compound that targets acyl-protein thioesterase-1 and/or -2.
  • a compound that targets acyl-protein thioesterase-1 and/or -2 is included in Table 4.
  • compounds comprising a target protein binding moiety are shown in Table 4.
  • “R” or a wavy line indicates an optional point of attachment to a linker or other molecule such as a DDB1 binding moiety.
  • heterobifunctional compounds Such compounds may be useful for a variety of purposes, including use as molecular glues or targeted protein degraders.
  • the heterobifunctional compound may be a small molecule.
  • the heterobifunctional compound may be included in a method described herein.
  • the heterobifunctional compound may be included in a pharmaceutical composition and administered to a subject.
  • a heterobifunctional compound described herein comprises a DNA damage-binding protein 1 (DDB1) binding moiety, a linker, and/or a target protein binding moiety.
  • a heterobifunctional compound described herein comprises a DDB1 binding moiety and a target protein binding moiety.
  • the heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • a DDB1 binding moiety is a natural product.
  • a DDB1 binding moiety is a synthetic product.
  • a target protein binding moiety is configured to bind a target protein.
  • a compound described herein comprises the structure of Formula (I) :
  • Z 1 is a target protein binding moiety
  • L 1 is a linker
  • Z 2 is a DDB1 binding moiety.
  • a compound described herein comprises the structure of Formula (IIc) :
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • a compound described herein comprises the structure of Formula (IId) :
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • a compound described herein comprises the structure of Formula (IIe) :
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl; wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • F 2 is aryl. In some embodiments of a compound of Formula (IIc-IIe) , F 2 is C 6 -C 12 aryl. In some embodiments of a compound of Formula (IIc-IIe) , F 2 is heteroaryl. In some embodiments of a compound of Formula (IIc-IIe) , F 2 is 5-12 membered heteroaryl.
  • F 2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.
  • F 2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl, and p is 1.
  • F 2 is 5-6 membered heteroaryl. In some embodiments of a compound of Formula (IIa) F 2 is heteroaryl, wherein the heteroaryl group has at least one nitrogen atom in the ring. In some embodiments of a compound of Formula (IIa) F 2 is heteroaryl, wherein the heteroaryl group has at least two nitrogen atoms in the ring. In some embodiments of a compound of Formula (IIa) F 2 is pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, F 2 is heteroaryl, wherein the heteroaryl group has at least one sulfur atom in the ring.
  • F 2 is heteroaryl, wherein the heteroaryl group has at least one oxygen atom in the ring.
  • F 2 is thiazolyl, oxazolyl, furyl, or thiophenyl.
  • F 2 is thiazolyl.
  • R 12 at each occurrence, is -NO 2 , halogen, methyl, halomethyl, phenyl, cyclopropyl, SO 2 CH 3 , or -CN.
  • R 12 is -NO 2 .
  • R 12 at each occurrence, is chloro or bromo.
  • q is 1.
  • q is 2. In some embodiments of a compound of Formula (IIc-IIe) , the linker is a bond. In some embodiments of a compound of Formula (IIc-IIe) , the linker is not a bond.
  • the compound binds to DDB1 via the DDB1 binding moiety.
  • the compound is bound to DDB1 via the DDB1 binding moiety.
  • a target protein binding moiety recruits a target protein which is ubiquitinated by a complex comprising DDB1.
  • the target protein is subsequently degraded.
  • the target protein may, in some instances, be any protein desirable for protein binding or degradation.
  • the target protein may include any protein that may be subjected to proteasomal degradation, or may include any protein that is useful to be bound by a ligand described herein.
  • the target protein comprises a target protein described herein.
  • the target protein binding moiety comprises a CBP binding moiety.
  • the target protein binding moiety comprises a p300 binding moiety.
  • the target protein binding moiety is a TrkA binding moiety.
  • the target protein binding moiety is a TrkB binding moiety.
  • the target protein binding moiety is a TrkC binding moiety.
  • the target protein binding moiety is a CDK4 binding moiety.
  • the target protein binding moiety is a CDK6 binding moiety. In some embodiments, the target protein binding moiety is a MEK1 binding moiety. In some embodiments, the target protein binding moiety is a MEK2 binding moiety. In some embodiments, the target protein binding moiety is a transcriptional coactivator. In some embodiments, the target protein binding moiety is a BRD4 binding moiety.
  • a compound may include any aspect of a compound shown in Table 5, such as a DDB1 binding moiety, a linker, or a target protein binding moiety of a compound shown in Table 5.
  • compounds comprising a DDB1 binding moiety, a linker, and a target protein binding moiety are shown in Table 5.
  • the compounds described herein may be useful for binding DNA damage-binding protein 1 (DDB1) , binding and/or degrading target proteins, for inducing subsequent cellular effects, and/or for inhibiting microbes such as a virus or a bacteria.
  • the compound is used as an antiviral drug.
  • a compound such as compound comprising a ligand described herein may compete with one or more viral proteins.
  • the compound is used as an antiparasitic drug.
  • the compound is used as a molecular glue, for example, to hold two molecules together such as DDB1 proteins and/or target proteins.
  • the compound is used as a degrader.
  • a heterobifunctional compound described herein may be used as targeted protein degrader.
  • the compounds used in the chemical reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature.
  • “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA) , Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka) , Apin Chemicals Ltd. (Milton Park, UK) , Avocado Research (Lancashire, U.K. ) , BDH Inc. (Toronto, Canada) , Bionet (Cornwall, U.K. ) , Chemservice Inc. (West Chester, PA) , Crescent Chemical Co.
  • the compounds described herein are prepared using the general methods in the art of organic synthesis, as described in the Examples section. Alternative synthetic methods are also used to generate the compounds described herein. Some embodiments include a method of making a heterobifunctional compound disclosed herein.
  • the compounds described herein are used to treat a subject. In certain embodiments, the compounds described herein are used to degrade a target protein. Some embodiments include administering a compound described herein to a subject.
  • the compound may be any ligand described herein.
  • Some embodiments include administering a pharmaceutical composition comprising a compound described herein to a subject. Some embodiments include providing a compound or pharmaceutical composition described herein for administration to a subject.
  • a modified protein disclosed herein is formed in vivo upon administration of the compound or pharmaceutical composition to the subject.
  • a ligand-protein complex disclosed herein is formed by administration of the compound or pharmaceutical composition to the subject.
  • the compound as described herein is administered as a pure chemical.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005) ) .
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising at least one compound described herein, or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier (s) or excipient (s) ) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.
  • the excipient comprises a buffer or solution.
  • a compound described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Some embodiments include use of a compound such as a ligand described herein, use of a ligand-DDB1 complex, or use of an in vivo modified DDB1 protein.
  • the use may include a use as an anti-viral drug.
  • the use may include a use as a molecule glue.
  • the use may include a use as a targeted protein degrader.
  • the use comprises administration of the compound to a subject.
  • the use comprises contact of a sample with the compound.
  • a method for degrading a target protein in a subject includes administering, to the subject, a ligand described herein. Some embodiments include administering, to the subject, a ligand comprising a DNA damage-binding protein 1 (DDB1) binding moiety covalently connected through a linker to a target protein binding moiety.
  • the subject is a subject in need of administration of the ligand, or is in need of treatment with the ligand.
  • Some embodiments include a method of modulating a target protein, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) , to a subject in need thereof.
  • the target protein is decreased in the subject, relative to a baseline measurement.
  • a target protein measurement may be decreased in a tissue sample or fluid sample from the subject, relative to a baseline target protein measurement in a first tissue sample or fluid sample from the subject.
  • Some embodiments include obtaining a baseline measurement of a target protein.
  • the baseline measurement may be obtained in a first sample obtained prior to administration of a compound described herein to a subject.
  • the first sample may comprise a fluid sample.
  • the first sample may comprise a tissue sample.
  • the baseline measurement may be obtained directly in the subject.
  • the baseline measurement may include a concentration.
  • the baseline measurement may be normalized, for example to a sample weight, to a sample volume, to a total sample protein measurement, or to a housekeeping protein measurement.
  • Some embodiments include obtaining a measurement of a target protein.
  • the measurement may be obtained in a second sample obtained after to administration of a compound described herein to a subject.
  • the measurement may be obtained in a second sample obtained during to administration of a compound described herein to a subject.
  • the second sample may comprise a fluid sample.
  • the second sample may comprise a tissue sample.
  • the measurement may be obtained directly in the subject.
  • the measurement may be normalized, for example to a sample weight, to a sample volume, to a total sample protein measurement, or to a housekeeping protein measurement.
  • Measurements or baseline measurements of target proteins may include any method known in the art.
  • a measurement or baseline measurements may be obtained using an assay such as an immunoassay, a colorimetric assay, a lateral flow assay, a fluorescence assay, a proteomics assay, or a cell-based assay.
  • the immunoassay may include an immunoblot such as a western blot or a dot blot, an enzyme-linked immunosorbent assay, or immunostaining.
  • the proteomics assay may include mass spectrometry.
  • a measurement or baseline measurements may be obtained using flow cytometry.
  • a measurement or baseline measurements may be obtained using chromatrography, for example high performance liquid chromatography.
  • the target protein may be or include any target protein included herein, as well as other target proteins not named.
  • Some embodiments include a method of degrading a cyclin dependent kinase (CDK) .
  • Some embodiments include a method of degrading a target protein comprising a CDK.
  • Some examples of such cyclin dependent kinases include, but are not limited to, CDK4 or CDK6.
  • Some embodiments include a method of modulating a CDK, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) , to a subject in need thereof.
  • the CDK is decreased in the subject, relative to a baseline measurement.
  • Some embodiments include measuring a decrease in the CDK following the administration.
  • Some embodiments include a method of degrading a cyclin. Some embodiments include a method of degrading a target protein comprising a cyclin. Some examples of such cyclins include cyclin D such as cyclin D1, or cyclin D2, cyclin D3, or cyclin E. Some embodiments include a method of modulating a cyclin, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) , to a subject in need thereof. Some embodiments include a method of modulating Cyclin D, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) , to a subject in need thereof. In some embodiments, the cyclin is decreased in the subject, relative to a baseline measurement. Some embodiments include measuring a decrease in the cyclin following the administration.
  • Some embodiments include a method of degrading a transcription factor.
  • transcription factors include CBP and P300.
  • Some embodiments include a method of degrading a target protein comprising CBP or P300.
  • Some embodiments include a method of degrading a target protein comprising CBP.
  • Some embodiments include a method of degrading a target protein comprising P300.
  • Some embodiments include a method of modulating a transcription factor, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) , to a subject in need thereof.
  • the transcription factor is decreased in the subject, relative to a baseline measurement.
  • Some embodiments include measuring a decrease in the transcription factor following the administration. Additional examples of target proteins are included herein.
  • subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans.
  • the subject is a mammal. In some embodiments, the subject is a human.
  • administering the ligand to the subject comprises administering an effective amount of the ligand sufficient to degrade the target protein.
  • the target protein upon administration of the ligand to the subject, is ubiquitinated to form a ubiquitinated target protein.
  • the administration is intravenous.
  • the administration comprises an injection.
  • the administration comprises cutaneous administration.
  • the administration comprises subcutaneous administration.
  • the administration comprises intraperitoneal administration.
  • the administration comprises oral administration.
  • the route of administration is intravenous, oral, subcutaneous, intraperitoneal, ocular, intraocular, intramuscular, interstitial, intraarterial, intracranial, intraventricular, intrasynovial, transepithelial, transdermal, by inhalation, ophthalmic, sublingual, buccal, topical, dermal, rectal, nasal, by insufflation, or by nebulization.
  • the administration is intramuscular.
  • the administration is intrathecal.
  • the administration is subcutaneous.
  • the administration is oral.
  • the administration is sublingual.
  • the administration is buccal.
  • the administration is rectal.
  • the administration is vaginal. In some embodiments, the administration is ocular. In some embodiments, the administration is otic. In some embodiments, the administration is nasal. In some embodiments, the administration is inhalation. In some embodiments, the administration is nebulization. In some embodiments, the administration is cutaneous. In some embodiments, the administration is topical. In some embodiments, the administration is transdermal. In some embodiments, the administration is systemic.
  • a method for degrading a target protein in a sample includes contacting a target protein with a ligand described herein. Some embodiments include contacting a target protein with a ligand comprising a DNA damage-binding protein 1 (DDB1) binding moiety covalently connected through a linker to a target protein binding moiety.
  • DDB1 DNA damage-binding protein 1
  • the sample is a biological sample.
  • the biological sample comprises a tissue, a cell, or a biological fluid.
  • the contact is in vitro. In some embodiments, the contact is in vivo.
  • the target protein upon being contacted with the ligand, is ubiquitinated to form a ubiquitinated target protein.
  • the ubiquitinated target protein upon administration or contact, is degraded. In some embodiments, the ubiquitinated target protein is degraded. In some embodiments, the degradation of the target protein is specific to the target protein. In some embodiments, the target protein comprises proteasomal degradation. In some embodiments, the target protein is degraded by a proteasome.
  • the ligand upon administration or contact, binds to a DDB1 protein to form a ligand-DDB1 complex. In some embodiments, the ligand directly binds to the DDB1 protein through the DDB1 binding moiety of the ligand. In some embodiments, the binding between the DDB1 binding moiety and the DDB1 protein is non-covalent. In some embodiments, the binding between the DDB1 binding moiety and the DDB1 protein is covalent. In some embodiments, the target protein is ubiquitinated by a ubiquitin E3 ligase complex comprising the DDB1 protein. In some embodiments, the ligand (e.g.,
  • a DDB1 ligand recruits the ubiquitin E3 ligase complex to the target protein via the DDB1 binding moiety.
  • the ligand is a small molecule.
  • the ligand comprises a targeted protein degrader.
  • the ligand is synthetic.
  • the ligand comprises a ligand described herein.
  • the target protein to degraded using a method described herein may be or include any target protein described herein.
  • the target protein comprises any one of a transcription factor, CBP, p300, a kinase, a receptor, a TRK, TrkA, TrkB, TrkC, a cyclin dependent kinase, CDK4, CDK6, B7.1, B7, TINFRlm, TNFR2, NADPH oxidase, a partner in an apoptosis pathway, BclIBax, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, a receptor, a 5HT receptor, a dop
  • a compound such as a compound comprising a DDB1 binding moiety may be useful 1) as an antiviral drug; 2) as a DDB1 protein level modulator (e.g. increasing or decreasing DDB1 protein levels) ; 3) as a DDB1 function modulator (e.g. activating or inhibiting DDB1) ; 4) as a molecular glue (e.g.
  • a compound described herein may be useful for treating a disease or disorder.
  • the compound may be administered to a subject having the disease or disorder.
  • the administration may reduce the severity of the disease or disorder in the subject, relative to a baseline measurement.
  • the compound may bind a target protein involved in the disease or disorder, resulting in inhibition or degradation of the target protein.
  • the compound may be a heterobifunctional compound, and comprise a DDB1 binding moiety and a target protein binding moiety, wherein the target protein is involved in the disease or disorder.
  • the target protein may exacerbate the disease or disorder.
  • the target protein may prevent or decrease inhibition of the disease or disorder.
  • a compound described herein is used as an antimicrobial drug.
  • the compound may be administered to a subject having a microbial infection.
  • the administration may reduce the severity of the microbial infection in the subject, relative to a baseline measurement.
  • the compound may bind a target protein involved in the microbial infection, resulting in inhibition or degradation of the target protein.
  • the microbial infection may include a virus infection.
  • the microbial infection may include a bacterial infection.
  • the compound may be a heterobifunctional compound, and comprise a DDB1 binding moiety and a target protein binding moiety, wherein the target protein is a microbial protein.
  • the microbial protein may include a viral protein.
  • the microbial protein may include a bacterial protein.
  • the target protein may be a non-microbial protein that exacerbates the microbial infection.
  • the target protein may be a non-microbial protein that prevents or decreases inhibition of the microbial infection.
  • the compound enters a cell of the subject, binds to a microbial protein in the cell via its target protein binding moiety, binds DDB1 via its DDB1 binding moiety, and induces ubiquitin-mediated degradation of the microbial protein. Such an action may be useful against microbes such as bacteria or viruses that infect or reside within the cell.
  • a compound described herein may be useful for modulating DDB1 protein levels.
  • the compound may be used to increase or decrease DDB1 protein levels.
  • a compound comprising a DDB1 binding moiety described herein is used to increase DDB1 protein levels.
  • the compound may bind to DDB1 and prevent its degradation.
  • a compound comprising a DDB1 binding moiety described herein is used to decrease DDB1 protein levels.
  • the compound may bind to DDB1 and increase its degradation.
  • the compound may be a heterobifunctional compound, and include a DDB1 binding moiety coupled to (directly or through a linker) a second moiety that increases degradation of the DDB1 protein, or that decreases degradation of the DDB1 protein.
  • the second moiety may accomplish this by binding to a target protein.
  • the target protein may include an E3 ubiquitin ligase protein that enhances degradation of the DDB1 protein.
  • the compound is not a heterobifunctional compound.
  • the compound comprises or consists of a DDB1 binding moiety.
  • the compound comprises or consists of the structure of Formula (II) , a compound provided in Table 1, or a derivative or salt thereof.
  • the compound is administered to a subject to increase a DDB1 protein level in the subject.
  • the administration may increase DDB1 activity in the subject, relative to a baseline measurement.
  • the compound is administered to a subject to decrease a DDB1 protein level in the subject.
  • the administration may decrease DDB1 activity in the subject, relative to a baseline measurement.
  • a compound described herein may be useful for modulating DDB1 function.
  • the compound may be used to activate or inhibit DDB1.
  • a compound comprising a DDB1 binding moiety described herein is used to increase DDB1 activity.
  • the compound may bind to DDB1 and activate DDB1.
  • the compound may allosterically activate DDB1.
  • the compound may activate DDB1 by binding to a protein binding site on DDB1.
  • a compound comprising a DDB1 binding moiety described herein is used to decrease DDB1 activity.
  • the compound may bind to DDB1 and inhibit DDB1.
  • the compound may allosterically inhibit DDB1.
  • the compound may inhibit DDB1 by binding to an active site of DDB1.
  • the compound may inhibit DDB1 by binding to a protein binding site on DDB1.
  • the compound may be a heterobifunctional compound, and include a DDB1 binding moiety coupled to (directly or through a linker) a second moiety that increases activity of the DDB1 protein, or that decreases activity of the DDB1 protein.
  • the second moiety may accomplish this by binding to a target protein.
  • the compound is administered to a subject to increase DDB1 activity in the subject.
  • the administration may increase DDB1 activity in the subject, relative to a baseline measurement.
  • the compound is administered to a subject to decrease DDB1 activity in the subject.
  • the administration may decrease DDB1 activity in the subject, relative to a baseline measurement.
  • a compound described herein may be useful as a molecular glue.
  • the compound may bind multiple molecules and hold them together.
  • the molecular glue binds DDB1 and a target protein.
  • the compound may accomplish this as a heterobifunctional compound that comprises a DDB1 binding moiety and a target protein binding moiety.
  • the compound may increase a protein-protein interaction between DDB1 and a target protein.
  • the compound may act as a molecular glue to modulate an activity or amount of the target protein.
  • the compound may decrease an amount of the target protein.
  • the compound may increase an amount of the target protein.
  • the compound may decrease activity of the target protein.
  • the compound may increase activity of the target protein.
  • the compound may increase activity of the target protein.
  • the method may include degrading the target protein through direct binding of an intermediate protein (e.g. a first protein) that interacts with the target protein. This may be referred to as bridged degradation.
  • Some embodiments include administering a binding molecule to the cell.
  • the binding molecule may include a ligand or compound disclosed herein.
  • the ligand may be a heterobifunctional compound.
  • the binding molecule may bind a first protein that interacts with the target protein.
  • the target protein may be degraded before the first protein. In some embodiments, the first protein is not degraded.
  • Some embodiments include administering, to the cell, a binding molecule that binds a first protein that interacts with the target protein, thereby degrading target protein, wherein the target protein is degraded before the first protein or wherein the first protein is not degraded. Some embodiments include measuring the target protein in the cell. Some embodiments include measuring the first protein in the cell. In some embodiments include measuring the first protein in the cell. In some embodiments, the interaction between the target protein and the first protein is binding. In some embodiments, the interaction between the target protein and the first protein is dimerization.
  • the target protein may include a target protein described herein.
  • the first protein may include another target protein described herein. In some embodiments, the target protein comprises a cyclin. In some embodiments, the target protein comprises Cyclin D.
  • the Cyclin D comprises Cyclin D1, Cyclin D2, or Cyclin D3.
  • the cyclin D may include Cyclin D1.
  • the cyclin D may include Cyclin D2.
  • the cyclin D may include Cyclin D3.
  • the first protein comprises a cyclin-dependent kinase (CDK) .
  • the CDK may include CDK4.
  • the CDK may include CDK6.
  • the first protein comprises CDK4 or CDK6.
  • the binding molecule reduces viability of the cell.
  • the cell is a eukaryotic cell.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • the cell is a cancer cell.
  • administering the binding molecule to the cell comprises administering the binding molecule to a subject comprising the cell.
  • the binding molecule recruits a ubiquitin E3 ligase that ubiquitinates the target protein.
  • the E3 ubiquitin ligase comprises DNA damage-binding protein 1 (DDB1) or Von Hippel–Lindau tumor suppressor (VHL) .
  • the E3 ubiquitin ligase may include DDB1.
  • the E3 ubiquitin ligase may include VHL.
  • the binding molecule comprises a heterobifunctional compound comprising an E3 ubiquitin ligase-binding moiety covalently connected through a linker to a first protein binding moiety.
  • the first protein binding moiety may include a target protein binding moiety disclosed herein.
  • the binding molecule comprises a structure disclosed herein.
  • a bridged degradation method comprising administering to a cell a binding molecule that binds a cyclin-dependent kinase (CDK) , thereby degrading a cyclin that interacts with the CDK.
  • the cyclin is degraded before the CDK, or wherein the CDK is not degraded.
  • the cyclin is degraded before the CDK.
  • the CDK is not degraded.
  • Some embodiments include measuring the cyclin in the cell.
  • Some embodiments include measuring the CDK in the cell.
  • the interaction between the cyclin and the CDK comprises binding or dimerization.
  • the interaction may include binding.
  • the interaction may include dimerization.
  • the cyclin comprises Cyclin D.
  • the Cyclin D comprises Cyclin D1, Cyclin D2, or Cyclin D3.
  • the cyclin D may include Cyclin D1.
  • the cyclin D may include Cyclin D2.
  • the cyclin D may include Cyclin D3.
  • the CDK comprises CDK4 or CDK6.
  • the CDK may include CDK4.
  • the CDK may include CDK6.
  • the binding molecule reduces viability of the cell.
  • the cell is a eukaryotic cell.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • the cell is a cancer cell.
  • administering the binding molecule to the cell comprises administering the binding molecule to a subject comprising the cell.
  • the binding molecule recruits a ubiquitin E3 ligase that ubiquitinates the cyclin.
  • the E3 ubiquitin ligase comprises DNA damage-binding protein 1 (DDB1) or Von Hippel–Lindau tumor suppressor (VHL) .
  • the E3 ubiquitin ligase may include DDB1.
  • the E3 ubiquitin ligase may include VHL.
  • the binding molecule comprises a heterobifunctional compound comprising an E3 ubiquitin ligase-binding moiety covalently connected through a linker to a CDK binding moiety.
  • the E3 ubiquitin ligase-binding moiety comprises a chemical structure disclosed herein.
  • the CDK binding moiety comprises a target protein binding moiety disclosed herein.
  • the binding molecule comprises a ligand disclosed herein.
  • Some embodiments include any one of the following:
  • a ligand-DNA damage-binding protein 1 (DDB1) complex formed by binding a DDB1 protein directly to a DDB1 ligand, the DDB1 ligand comprising a DDB1 binding moiety.
  • beta propeller domain comprises a beta propeller C (BPC) domain.
  • ligand-DDB1 complex of any one of embodiments 2-5, wherein the binding region on the DDB1 protein comprises one or more of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • DDB1 residues ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG
  • ligand-DDB1 complex of any one of embodiments 1-6, wherein one or more of the following DDB1 residues are involved in the binding between the DDB1 protein and the DDB1 ligand: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033.
  • ligand-DDB1 complex of any one of embodiments 1-8, wherein the binding between the DDB1 protein and the DDB1 ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) below 100 ⁇ M, a Kd below 90 ⁇ M, a Kd below 80 ⁇ M, a Kd below 70 ⁇ M, a Kd below 60 ⁇ M, a Kd below 50 ⁇ M, a Kd below 45 ⁇ M, a Kd below 40 ⁇ M, a Kd below 35 ⁇ M, a Kd below 30 ⁇ M, a Kd below 25 ⁇ M, a Kd below 20 ⁇ M, a Kd below 15 ⁇ M, a Kd below 14 ⁇ M, a Kd below 13 ⁇ M, a Kd below 12 ⁇ M, a Kd below 11 ⁇ M, a Kd below 10 ⁇ M, a Kd below 9 ⁇ M, a Kd below 8 ⁇ M, a Kd below 7
  • ligand-DDB1 complex of any one of embodiments 1-9, wherein the binding between the DDB1 protein and the DDB1 ligand comprises a binding affinity with a Kd ⁇ 20 uM, a Kd from 20-100 uM, or a Kd > 100 uM.
  • ligand-DDB1 complex of any one of embodiments 1-12, wherein the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected through a linker to a target protein binding moiety.
  • F 1 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • a 4 and A 5 are each independently CR 12 , S, N, or O, wherein at least one of A 4 or A 5 is N, S, or O.
  • Z 1 is a target protein binding moiety
  • L 1 is a linker
  • Z 2 is a DDB1 binding moiety.
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl; wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • DDB1 DNA damage-binding protein 1
  • beta propeller domain comprises a beta propeller C (BPC) domain.
  • DDB1 residues ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG72
  • the binding between the DDB1 protein and the DDB1 ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) below 100 ⁇ M, a Kd below 90 ⁇ M, a Kd below 80 ⁇ M, a Kd below 70 ⁇ M, a Kd below 60 ⁇ M, a Kd below 50 ⁇ M, a Kd below 45 ⁇ M, a Kd below 40 ⁇ M, a Kd below 35 ⁇ M, a Kd below 30 ⁇ M, a Kd below 25 ⁇ M, a Kd below 20 ⁇ M, a Kd below 15 ⁇ M, a Kd below 14 ⁇ M, a Kd below 13 ⁇ M, a Kd below 12 ⁇ M, a Kd below 11 ⁇ M, a Kd below 10 ⁇ M, a Kd below 9 ⁇ M, a Kd below 8 ⁇ M, a Kd below 7
  • Kd equilibrium dissociation constant
  • Z 1 is a target protein binding moiety
  • L 1 is a linker
  • Z 2 is a DDB1 binding moiety.
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl; wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • a ligand comprising a DNA damage-binding protein 1 (DDB1) binding moiety.
  • DDB1 DNA damage-binding protein 1
  • ligand of any one of embodiments 86-88, wherein the binding between the DDB1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 uM, a Kd from 20-100 uM, or a Kd >100 uM.
  • F 1 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • a 4 and A 5 are each independently S, N, or O, wherein at least one of A 4 or A 5 is N.
  • 105 The ligand of any one of embodiments 93-104, wherein s is 1 or 2.
  • Z 1 is a target protein binding moiety
  • L 1 is a linker
  • Z 2 is a DDB1 binding moiety.
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • F 2 is aryl, heteroaryl, carbocyclyl, or heterocyclyl
  • each R a is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 carbocyclyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl; wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • s 1-5;
  • L 1 is a linker
  • Z 1 is a target protein binding moiety.
  • a method for degrading a target protein in a subject comprising:
  • a heterobifunctional compound comprising a DNA damage-binding protein 1 (DDB1) binding moiety covalently connected through a linker to a target protein binding moiety.
  • DDB1 DNA damage-binding protein 1
  • any one of embodiments 128-130 wherein the route of administration is intravenous, oral, subcutaneous, intraperitoneal, ocular, intraocular, intramuscular, interstitial, intraarterial, intracranial, intraventricular, intrasynovial, transepithelial, transdermal, by inhalation, ophthalmic, sublingual, buccal, topical, dermal, rectal, nasal, by insufflation, or by nebulization.
  • administering the compound to the subject comprises administering an effective amount of the compound sufficient to degrade the target protein.
  • a method for degrading a target protein in a sample comprising:
  • a heterobifunctional compound comprising a DNA damage-binding protein 1 (DDB1) binding moiety covalently connected through a linker to a target protein binding moiety.
  • DDB1 DNA damage-binding protein 1
  • the biological sample comprises a tissue, a cell, or a biological fluid.
  • the target protein comprises any one of a transcription factor, CBP, p300, a kinase, a receptor, a TRK, TrkA, a cyclin dependent kinase, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, a cyclin, cyclin A, cyclin B, cyclin C, cyclin D, cyclin D1, cyclin D2, cyclin D3, cyclin E, cyclin H, cyclin K, cyclin T, cyclin T1, p25, p35, B7.1, B7, TINFRlm, TNFR2, NADPH oxidase, a partner in an apoptosis pathway, BclIBax, C5a receptor, HMG-CoA reductase, PDE V
  • a method for degrading a target protein in a cell comprising:
  • a binding molecule that binds a first protein that interacts with the target protein, thereby degrading target protein, wherein the target protein is degraded before the first protein or wherein the first protein is not degraded.
  • Cyclin D comprises Cyclin D1, Cyclin D2, or Cyclin D3.

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PCT/CN2021/096782 2020-05-28 2021-05-28 Modified proteins and protein degraders Ceased WO2021239117A1 (en)

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JP2022573579A JP2023529099A (ja) 2020-05-28 2021-05-28 修飾タンパク質およびタンパク質分解誘導薬
CN202180058377.0A CN116472292A (zh) 2020-05-28 2021-05-28 经修饰的蛋白质和蛋白质降解剂
EP21812627.4A EP4157888A4 (en) 2020-05-28 2021-05-28 MODIFIED PROTEINS AND PROTEIN DEGRADATION AGENTS
US17/496,628 US20230057177A1 (en) 2020-05-28 2021-10-07 Modified proteins and protein degraders
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WO2022218239A1 (zh) * 2021-04-12 2022-10-20 杜心赟 新型噻唑类化合物及其制备方法和用途
WO2023061440A1 (en) * 2021-10-14 2023-04-20 Cullgen (Shanghai), Inc. Modified proteins and protein degraders
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
WO2024183798A1 (en) * 2023-03-07 2024-09-12 Cullgen Inc. Compounds and methods of treating cancers
WO2025054361A1 (en) * 2023-09-05 2025-03-13 Apellis Pharmaceuticals, Inc. Complement inhibition
EP4628488A4 (en) * 2022-12-16 2026-01-21 Adlai Nortye Biopharma Co Ltd CYCLINE K DEGRADING AGENT AND ITS USE

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WO2017089763A1 (en) * 2015-11-23 2017-06-01 Immunocore Limited Peptides
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WO2020077278A1 (en) * 2018-10-12 2020-04-16 The Scripps Research Institute Compounds and methods for dcaf-mediated protein degradation

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US12247021B2 (en) 2019-12-06 2025-03-11 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
WO2022218239A1 (zh) * 2021-04-12 2022-10-20 杜心赟 新型噻唑类化合物及其制备方法和用途
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US12258333B2 (en) 2021-06-04 2025-03-25 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
WO2023061440A1 (en) * 2021-10-14 2023-04-20 Cullgen (Shanghai), Inc. Modified proteins and protein degraders
EP4628488A4 (en) * 2022-12-16 2026-01-21 Adlai Nortye Biopharma Co Ltd CYCLINE K DEGRADING AGENT AND ITS USE
WO2024183798A1 (en) * 2023-03-07 2024-09-12 Cullgen Inc. Compounds and methods of treating cancers
WO2025054361A1 (en) * 2023-09-05 2025-03-13 Apellis Pharmaceuticals, Inc. Complement inhibition

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JP2023529099A (ja) 2023-07-07
CN116472292A (zh) 2023-07-21
US20230057177A1 (en) 2023-02-23

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