Stabilized SOS1 peptides
First Claim
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1. An internally cross-linked polypeptide comprising the amino acid sequence A0B0C0D0E0F0G0 A1B1C1D1E1F1G1 A2B2 (SEQ ID NO:
- 1) wherein;
A0 is F;
B0 is F;
C0 is G;
D0 is I;
E0 is Y;
F0 is L;
G0 is T;
A1 is N;
B1 is I;
C1 is L, K, or K substituted with a guanine nucleoside or guanine nucleoside analog;
D1 is K or R;
E1 is T;
F1 is E;
G1 is E, K, or K substituted with a guanine nucleoside or guanine nucleoside analog;
A2 is G; and
B2 is N;
wherein the side chains of two amino acids of SEQ ID NO;
1 separated by three or six amino acids are cross-linked by an internal hydrocarbon staple; and
wherein the internally cross-linked polypeptide binds a wild type KRAS protein.
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Abstract
Provided herein are polypeptides containing stabilized therapeutic peptides related to KRAS guanidine exchange factor (SOS1). Also provided are compositions containing these polypeptides and methods of using such peptides in the treatment of cancer that includes administering to a subject one of the polypeptides. This disclosure relates to structurally stabilized therapeutic peptides related to KRAS guanidine exchange factor (SOS1), and methods of using such peptides in the treatment of cancer.
6 Citations
24 Claims
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1. An internally cross-linked polypeptide comprising the amino acid sequence A0B0C0D0E0F0G0 A1B1C1D1E1F1G1 A2B2 (SEQ ID NO:
- 1) wherein;
A0 is F; B0 is F; C0 is G; D0 is I; E0 is Y; F0 is L; G0 is T; A1 is N; B1 is I; C1 is L, K, or K substituted with a guanine nucleoside or guanine nucleoside analog; D1 is K or R; E1 is T; F1 is E; G1 is E, K, or K substituted with a guanine nucleoside or guanine nucleoside analog; A2 is G; and B2 is N; wherein the side chains of two amino acids of SEQ ID NO;
1 separated by three or six amino acids are cross-linked by an internal hydrocarbon staple; andwherein the internally cross-linked polypeptide binds a wild type KRAS protein. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23)
- 1) wherein;
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15. An internally cross-linked polypeptide that binds a wild type KRAS protein, the internally cross-linked polypeptide comprising the amino acid sequence A0B0C0D0E0F0G0 A1B1C1D1E1F1G1 A2B2 (SEQ ID NO:
- 1) wherein;
A0 is F, Z or X; B0 is F, X, Z, or E; C0 is G or D; D0 is I or K; E0 i s Y or X; F0 is L, X, R, or D; G0 is T, L, or E; A1 is N, X, or R; B1 is I or X; C1 is L, C, E, K, or K substituted with a guanine nucleoside or guanine nucleoside analog; D1 is K or R; E1 is T or A; F1 is E or X; G1 is E, C, K, or K substituted with a guanine nucleoside or guanine nucleoside analog; A2 is G or A; and B2 is N; wherein X is a stapled amino acid and Z is (R)-2-amino-2-methyl-dec-9-enoic acid; wherein the side chains of two X or Z amino acids separated by three or six amino acids are cross-linked by an internal hydrocarbon staple; and wherein the K substituted with a guanine nucleoside or guanine nucleoside analog comprises; - View Dependent Claims (16, 17, 18, 19, 20, 24)
- 1) wherein;
Specification