Compositions and methods for treating cancer
K-Ras is the most frequently mutated oncogene in human cancer. Disclosed herein are compositions and methods for modulating K-Ras and treating cancer.
1. A human K-Ras protein having a cysteine at residue 12, wherein said cysteine is covalently bonded to a compound, wherein said compound has the formula
R 1 -L 1 -L 2 -L 3 -E,
wherein
R 1 is substituted or unsubstituted fused ring aryl or substituted or unsubstituted fused ring heteroaryl;
L 1 is a substituted or unsubstituted heteroarylene;
L 2 is a bond;
L 3 is a substituted or unsubstituted spirocyclic linker; and, prior to covalently bonding to the cysteine 12,
2. The human K-Ras protein of claim 1 , wherein R 1 is a substituted or unsubstituted fused ring heteroaryl.
3. The human K-Ras protein of claim 1 , wherein R 1 is a substituted or unsubstituted indazolyl, wherein the substituents are independently selected from methyl, —Cl, —NH 2 , —I, —CCH, —CH 2 CH 2 OH, —OCH 2 CCH, —CF 3 , —OCH 3 , —OH, —CH 2 CH 3 , —NHS(O) 2 CH 3 , —CH 2 NH 2 , —Br, isoxazolyl, —NHC(O)OC(CH 3 ) 3 , p-chlorophenyl, thiophenyl, —F, pyrazolyl, —CH 2 OH, —C(O)NHCH 2 CH 2 OH, —OCH 2 CH 2 OH, —S(O) 2 NH 2 , tetrazolyl, —CHCH 3 OH, —C(O)CH 3 , —C(O)H, —OCH 3 , —C(O)OH, —C(O)OCH 3 , —C(O)NH 2 , —N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHC(O)CH 3 , pyrrolidinyl, —OCH 2 CH 2 NH 2 , —C(O)N(CH 3 ) 2 , —NHCH 3 , —NHC(O)CH 3 , —CN, —C(O)OCH 3 , or
4. The human K-Ras protein of claim 2 , wherein L 1 is a substituted or unsubstituted monocyclic heteroarylene.
5. The human K-Ras protein of claim 2 , wherein L 1 is a substituted or unsubstituted pyrazolylene, wherein the substituents are independently selected from halogen, —CX c 3 , —CN, —SO 2 Cl, —SO n3 R 10c , —SO v3 NR 7c R 8c , —NHNH 2 , —ONR 7c CR 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7c R 8c , —N(O) m3 , —NR 7c R 8c , —C(O)R 9c , —C(O) OR 9c , —C(O)NR 7c R 8c , —OR 10c , —NR 7c SO 2 R 10c , —NR 7c ═(O)R 9c , —NR 7c C(O) OR 9c , —NR 7c OR 9c , —OCX c 3 , —OCHX c 2 , 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 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;
R 7c , R 8c , R 9c and R 10c are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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;
R 7c and R 8c substituents bonded to the same nitrogen atom may optionally be joined to Response to Non-Final Office Action form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
m3 and v3 are independently an integer from 1 to 2;
n3 is an integer from 0 to 4;
and X c is independently —Cl, —Br, —I, or —F.
6. The human K-Ras protein of claim 3 , wherein L 1 is a substituted or unsubstituted monocyclic heteroarylene.
7. The human K-Ras protein of claim 3 , wherein L 1 is a substituted or unsubstituted pyrazolylene, wherein the substituents are independently selected from halogen, —CX c 3 , —CN, —SO 2 Cl, —SO n3 R 10c , —SO v3 NR 7c R 8c , —NHNH 2 , —ONR 7 CR 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7c R 8c , —N(O) m3 , —NR 7c R 8c , —C(O)R 9c , —C(O) OR 9c , —C(O)NR 7c R 8c , —OR 10c , —NR 7c SO 2 R 10c , —NR 7c C═(O)R 9c , —NR 7c C(O) OR 9c , —NR 7c OR 9c , —OCX c 3 , OCHX c 2 , 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 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;
R 7c , R 8c , R 9c and R 10c are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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;
R 7c and R 8c substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
m3 and v3 are independently an integer from 1 to 2;
n3 is an integer from 0 to 4;
and X c is independently —Cl, —Br, —I, or —F.
8. The human K-Ras protein of claim 2 , wherein L 1 is a fused ring heteroarylene substituted with at least one substituent group.
9. The human K-Ras protein of claim 2 , wherein L 1 is 6,6-fused ring heteroarylene substituted with at least one substituent group.
10. The human K-Ras protein of claim 3 , wherein L 1 is a fused ring heteroarylene substituted with at least one substituent group.
11. The human K-Ras protein of claim 3 , wherein L 1 is 6,6-fused ring heteroarylene substituted with at least one substituent group.
12. The human K-Ras protein of claim 4 , wherein L 3 is a substituted or unsubstituted heterocyclic spirocyclic linker.
13. The human K-Ras protein of claim 5 , wherein L 3 is a substituted or unsubstituted heterocyclic spirocyclic linker.
14. The human K-Ras protein of claim 6 , wherein L 3 is a substituted or unsubstituted heterocyclic spirocyclic linker.
15. The human K-Ras protein of claim 7 , wherein L 3 is a substituted or unsubstituted heterocyclic spirocyclic linker.
16. The human K-Ras protein of claim 8 , wherein L 3 is a substituted or unsubstituted heterocyclic spirocyclic linker.
17. The human K-Ras protein of claim 9 , wherein L 3 is a substituted or unsubstituted heterocyclic spirocyclic linker.
18. The human K-Ras protein of claim 10 , wherein L 3 is a substituted or unsubstituted heterocyclic spirocyclic linker.
19. The human K-Ras protein of claim 11 , wherein L 3 is a substituted or unsubstituted heterocyclic spirocyclic linker.
20. The human K-Ras protein of claim 12 , wherein L 3 is an unsubstituted heterocyclic spirocyclic linker.
21. The human K-Ras protein of claim 13 , wherein L 3 is an unsubstituted heterocyclic spirocyclic linker.
22. The human K-Ras protein of claim 14 , wherein L 3 is an unsubstituted heterocyclic spirocyclic linker.
23. The human K-Ras protein of claim 15 , wherein L 3 is an unsubstituted heterocyclic spirocyclic linker.
24. The human K-Ras protein of claim 16 , wherein L 3 is an unsubstituted heterocyclic spirocyclic linker.
25. The human K-Ras protein of claim 17 , wherein L 3 is an unsubstituted heterocyclic spirocyclic linker.
26. The human K-Ras protein of claim 18 , wherein L 3 is an unsubstituted heterocyclic spirocyclic linker.
27. The human K-Ras protein of claim 19 , wherein L 3 is an unsubstituted heterocyclic spirocyclic linker.