Compositions and methods for treating cancer
AssigneeThe Regents of the University of California
InventorsJonathan Ostrem, Ulf Peters, Kevan M. Shokat
Life of this patent
Estimating the term…
Abstract
K-Ras is the most frequently mutated oncogene in human cancer. Disclosed herein are compositions and methods for modulating K-Ras and treating cancer.
Claims38
A compound having the formula:
- R1-L1-L2-L3-E
- wherein,
- R1 is a Switch 2-Binding Pocket binding moiety;
- L1 is a bond or a divalent radical chemical linker;
- L2 is a bond or a divalent radical chemical linker;
- L3 is a bond or a divalent radical chemical linker;
- E is an electrophilic chemical moiety capable of forming a covalent bond with a K-Ras cysteine residue or a K-Ras aspartate residue.
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A method of selectively modulating a Ras protein, said method comprising contacting said Ras protein with a compound which contacts at least one amino acid residue forming a Switch 2 binding pocket of said Ras protein, wherein said at least one amino acid residue is selected from valine-7, valine-9, glycine-10, proline-34, threonine-58, glycine-60, glutamine-61, glutamate-62, glutamate-63, arginine-68, tyrosine-71, methionine-72, tyrosine-96, glutamine-99 and isoleucine-100 of said Ras protein, and wherein said compound covalently reacts with an amino acid residue of said Ras protein.
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A compound having molecular dimensions compatible with the shape of a K-Ras Switch 2 binding pocket wherein the compound, when present in an aqueous solution comprising 200 μM of the compound and 4 μM K-Ras, covalently binds to at least 50% of K-Ras proteins present in solution after 24 hours.
A compound of Formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- e5 is an integer from 0 to 5;
- X′ is —O—, —NH—, or —S—;
- R2A and R2B are independently hydrogen, 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 substituent bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
- R3 is independently hydrogen, oxo, halogen, —CX3, —CN, —SO2Cl, —SOnR10, —SOvNR7R8, —NHNH2, —ONR7R8, —NHC═(O)NHNH2, —NHC═(O)NR7R8, N(O)m, —NR7R8, —C(O)R9, —C(O)—OR9, —C(O)NR7R8, —OR10, —NR7SO2R10, —NR7C═(O)R9, —NR7C(O)—OR9, —NR7OR9, —OCX3, —OCHX2, 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;
- L2 is independently R2C-substituted or unsubstituted cycloalkylene, R2C-substituted or unsubstituted heterocycloalkylene, R2C-substituted or unsubstituted arylene, R2C-substituted or unsubstituted heteroarylene, or R2C-substituted or unsubstituted spirocyclic linker;
- L3 is independently R2C-substituted or unsubstituted cycloalkylene, R2C-substituted or unsubstituted heterocycloalkylene, R2C-substituted or unsubstituted arylene, R2C-substituted or unsubstituted heteroarylene, or R2C-substituted or unsubstituted spirocyclic linker;
- E is an electrophilic chemical moiety capable of forming a covalent bond with a cysteine or aspartate residue;
- R2C is independently hydrogen, oxo,
- halogen, —CXc3, —CN, —SO2Cl, —SOn3R10c, —SOv3NR7cR8c, —NHNH2, —ONR7cR8c, —NHC═(O)NHNH2, —NHC═(O)NR7cR8c, —N(O)m3, —NR7cR8c, —C(O)R9c, —C(O)NR7cR8c, —OR10c, —NR7cSO2R10c, —NR7cC═(O)R9c, —NR7cC(O)—OR9c, —NR7cOR9c, —OCXc3, —OCHXc2, 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;
- two adjacent R2C substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- two R2C substituents bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
- R7, R8, R9, and R10 are independently hydrogen,
- halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, 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;
- R7a, R8a, R9a and R10a are independently hydrogen, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, 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;
- R7a and R8a substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- R7c, R8c, R9c and R10c are independently hydrogen,
- halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2Cl, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, 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;
- m, m1, m3, v, v1, and v3 are independently 1 or 2;
- n, n1, and n3 are independently an integer from 0 to 4;
- X, Xa and Xc are independently —Cl, —Br, —I, or —F.
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Dependencies are inferred from the claim text.