Compositions and methods for treating cancer

Patent metadata

Field	Value
Publication number	US-11008334-B2
Application number	US-201916720526-A
Country	US
Kind code	B2
Filing date	Dec 19, 2019
Priority date	Apr 10, 2012
Publication date	May 18, 2021
Grant date	May 18, 2021

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.

First claim

What is claimed is:

1. A K-Ras protein covalently bonded to a compound, wherein the compound is covalently bonded to cysteine residue 12 of the K-Ras protein and is in contact with one or more amino acid residues of a K-Ras protein Switch 2 binding pocket.

2. The K-Ras protein of claim 1 , wherein the one or more amino acid residues of the K-Ras protein Switch 2 binding pocket are selected from the group consisting of V7, V9, G10, K16, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.

3. The K-Ras protein of claim 1 , wherein the one or more amino acid residues of the K-Ras protein Switch 2 binding pocket comprise at least three amino acid residues selected from the group consisting of V7, V9, G10, K16, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.

4. The K-Ras protein of claim 1 , wherein the one or more amino acid residues of the K-Ras protein Switch 2 binding pocket are selected from the group consisting of K16, R68, M72, Y96, and Q99.

5. The K-Ras protein of claim 1 , wherein the compound has an electrophilic chemical moiety covalently bonded to cysteine residue 12 of the K-Ras protein, wherein the electrophilic chemical moiety is a substituted or unsubstituted acrylamide.

6. The K-Ras protein of claim 1 , wherein the compound has an electrophilic chemical moiety covalently bonded to cysteine residue 12 of the K-Ras protein, wherein electrophilic chemical moiety is:

wherein R 13 is hydrogen, halogen, —CX b 3 , or —CN; and X b is Cl, Br, I or F.

7. The K-Ras protein of claim 1 , wherein the compound has the formula:
R 1 -L 1 -L 2 -L 3 -E,
wherein:
R 1 is a Switch 2 Binding Pocket binding moiety;
L 1 is a bond or a divalent radical chemical linker;
L 2 is a bond;
L 3 is

f8 is an integer from 0 to 8;
R 2C is independently hydrogen or substituted or unsubstituted alkyl; and
E is an electrophilic chemical moiety covalently bonded with cysteine residue 12 of the K-Ras protein.

8. The K-Ras protein of claim 7 , wherein E is:

wherein R 13 is hydrogen, halogen, —CX b 3 , or —CN; and X b is Cl, Br, I or F.

9. The K-Ras protein of claim 7 , wherein:
R 1 is R 3 — substituted or unsubstituted aryl or R 3 -substituted or unsubstituted heteroaryl;
R 3 is independently hydrogen, oxo, halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 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 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —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;
m and v are independently 1 or 2;
n is independently an integer from 0 to 4; and
each X is independently —Cl, —Br, —I, or —F.

10. The K-Ras protein of claim 9 , wherein
R 1 is R 3 -substituted or unsubstituted aryl;
R 3 is independently oxo, halogen, —OR 10 , substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl.

Assignees

• Univ California

Inventors

• Ostrem Jonathan
• Peters Ulf
• Shokat Kevan M

Classifications

• C12Y306/05002

  Small monomeric GTPase (3.6.5.2) · CPC title

• A61K38/1709

  from mammals · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D207/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title