Protein-protein interaction stabilizers

A method of identifying a chemical compound that modulates binding of a protein to a client protein, the method comprising:

• contacting a client protein with a protein comprising a solvent exposed reactive amino acid side chain proximal to a client protein binding site, thereby forming a protein-client complex;
• contacting said protein-client complex with a first candidate compound thereby forming a conjugate-client complex, wherein said first candidate compound comprises a first candidate chemical moiety covalently bound to a first reactive group, wherein said first reactive group is specifically reactive with said solvent exposed reactive amino acid side chain, which is not a cysteine side chain, and wherein said first candidate compound covalently attaches to said solvent exposed reactive amino acid side chain to form said conjugate-client complex;
• and
• detecting a change in stability of said conjugate-client complex relative to the stability of said protein-client complex, wherein said protein-client complex comprises said client protein and said protein in the absence of said first candidate compound covalently bound to said solvent exposed reactive amino acid side chain, thereby identifying said first candidate compound as the first chemical compound that modulates binding of said protein to said client protein.

A method of identifying a chemical compound that modulates binding of a protein to a client protein, the method comprising:

• contacting a first candidate compound with a client protein comprising a solvent exposed reactive amino acid side chain, thereby forming a client protein conjugate, wherein said first candidate compound comprises a first candidate chemical moiety covalently bound to a first reactive group, wherein said first reactive group is specifically reactive with said solvent exposed reactive amino acid side chain;
• contacting said client protein conjugate with a protein thereby forming a conjugate-protein complex;
• and
• detecting a change in stability of said conjugate-protein complex relative to the stability of a protein-client complex, wherein said protein-client complex comprises said client protein and said protein in the absence of said first candidate compound covalently bound to said solvent exposed reactive amino acid side chain, thereby identifying said first candidate compound as the first chemical compound that modulates binding of said protein to said client protein.

A method of identifying a chemical compound that modulates binding of a protein to a client protein, the method comprising:

• contacting a protein with a client protein comprising a solvent exposed reactive amino acid side chain thereby forming a protein-client complex;
• contacting said protein-client complex with a first candidate compound thereby forming a conjugate-protein complex, wherein said first candidate compound comprises a first candidate chemical moiety covalently bound to a first reactive group, wherein said first reactive group is specifically reactive with said solvent exposed reactive amino acid side chain, and wherein said first candidate compound covalently attaches to said solvent exposed reactive amino acid side chain to form said conjugate-protein complex;
• and
• detecting a change in stability of said conjugate-protein complex relative to the stability of said protein-client complex, wherein said protein-client complex comprises said protein and said client protein in the absence of said first candidate compound covalently bound to said solvent exposed reactive amino acid side chain, thereby identifying said first candidate compound as the first chemical compound that modulates binding of said protein to said client protein.

A compound having the general formula:

• R1-L1-W-L3-R3,
• wherein:
• L1 and L3 are independently a bond, —S(O)2—, —NH—, —O—, —S—, —C(O)—, —NHS(O)2—, —S(O)2NH—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• R1 is hydrogen, halogen, —CX13, —CHX12, —CH2X1, —OCX13, —OCH2X1, —OCHX12, —CN, —SOn1R1D, —SOv1NR1AR1B, —NR1CNR1AR1B, —ONR1AR1B, —NHC(O)NR1CNR1AR1B, —NHC(O)NR1AR1B, —N(O)m1, —NR1AR1B, —C(O)R1C, —C(O)—OR1C, —C(O)NR1AR1B, —OR1D, —NR1ASO2R1D, —NR1AC(O)R1C, —NR1AC(O)OR1C, —NR1AOR1C, —SF5, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R1A, R1B, R1C, and R1D are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• W is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• R3 is -L3A-L3B-E3, hydrogen, halogen, —CX33, —CHX32, —CH2X3, —OCX33, —OCH2X3, —OCHX32, —CN, —SOn3R3D, —SOv3NR3AR3B, —NHC(O)NR3AR3B, —N(O)m3, —NR3AR3B, —C(O)R3C, —C(O)—OR3C, —C(O)NR3AR3B, —OR3D, —NR3ASO2R3D, —NR3AC(O)R3C, —NR3AC(O)OR3C, —NR3AOR3C, —SF5, —N3, —C(NR3C)NR3AR3B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• L3A is a bond, —S(O)2—, —NH—, —O—, —S—, —C(O)—, —NHS(O)2—, —S(O)2NH—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• L3B is a bond, —NH—, —C(O)NH—, —NHC(O)NH—, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted heteroarylene;
• E3 is —SH,
• R36, R37, and R38 are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COH, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• X1, X3, and X37 are independently —F, —Cl, —Br, or —I;
• n1 and n3 are independently an integer from 0 to 4;
• and
• m1, v1, m3, and v3 are independently 1 or 2.

A compound having the general formula:

• R2-L2-W-L3-R3
• wherein:
• L2 and L3 are independently a bond, —S(O)2—, —NH—, —O—, —S—, —C(O)—, —NHS(O)2—, —S(O)2NH—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• R2 is hydrogen, halogen, —CX23, —CHX22, —CH2X2, —OCX23, —OCH2X2, —OCHX22, —CN, —SOn2R2D, —SOv2NR2AR2B, —NR2CNR2AR2B, —ONR2AR2B, —NHC(O)NR2CNR2AR2B, —NHC(O)NR2AR2B, —N(O)m2, —NR2AR2B, —C(O)R2C, —C(O)—OR2C, —C(O)NR2AR2B, —OR2D, —NR2ASO2R2D, —NR2AC(O)R2C, —NR2AC(O)OR2C, —NR2AOR2C, —SF5, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R2A, R2B, R2C, and R2D are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• W is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• and
• R3 is -L3A-L3B-E3, hydrogen, halogen, —CX33, —CHX32, —CH2X3, —OCX33, —OCH2X3, —OCHX32, —CN, —SOn3R3D, —SOv3NR3AR3B, —NHC(O)NR3AR3B, —N(O)m3, —NR3AR3B, —C(O)R3C, —C(O)—OR3C, —C(O)NR3AR3B, —OR3D, —NR3ASO2R3D, —NR3AC(O)R3C, —NR3AC(O)OR3C, —NR3AOR3C, —SF5, —N3, —C(NR3C)NR3AR3B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• L3A is a bond, —S(O)2—, —NH—, —O—, —S—, —C(O)—, —NHS(O)2—, —S(O)2NH—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• L3B is a bond, —NH—, —C(O)NH—, —NHC(O)NH—, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted heteroarylene;
• E3 is —SH,
• R36, R37, and R38 are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COH, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• X2, X3, and X37 are independently —F, —Cl, —Br, or —I;
• n2 and n3 are independently an integer from 0 to 4;
• and
• m2, v2, m3, and v3 are independently 1 or 2.