Stablized EZH2 peptides
Provided herein are polypeptides containing stabilized therapeutic peptides related to enhancer of zeste homolog 2 (EZH2), histone lysine N-methyltransferase. Also provided are compositions containing these polypeptides and methods of using such peptides in the treatment of cancer that include administering to a subject one of the polypeptides.
1. An internally cross-linked polypeptide that inhibits the interaction between Enhancer of Zeste Homolog 2 (EZH2) and Embryonic Ectoderm Development (EED), the internally cross-linked polypeptide comprising the amino acid sequence FSSNRX 1 KILX 2 RTEILNQEWKQRRIQPV (SEQ ID NO:26), wherein X 1 and X 2 are each a non-natural amino acid with an olefinic side chain, and wherein the internally cross-linked polypeptide is cell penetrant.
2. The internally cross-linked polypeptide of claim 1 , wherein X 1 and X 2 are each (S)-2-(4′-pentenyl) alanine (S5).
3. The internally cross-linked polypeptide of claim 2 , wherein the internally cross-linked polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 26.
4. A pharmaceutical composition comprising the internally cross-linked polypeptide of claim 3 and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4 , further comprising an inhibitor of EZH2 enzymatic activity.
6. The pharmaceutical composition of claim 5 , wherein the inhibitor of EZH2 enzymatic activity is GSK126.
7. A method of treating an EZH2-overexpressing or EZH2-dependent cancer in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the internally cross-linked polypeptide of claim 1 .
8. The method of claim 7 , further comprising administering to the human subject an inhibitor of EZH2 enzymatic activity.
9. An internally cross-linked polypeptide that inhibits the interaction between Enhancer of Zeste Homolog 2 (EZH2) and Embryonic Ectoderm Development (EED), the internally cross-linked polypeptide comprising the amino acid sequence FSSNRX 1 KILX 2 RTQILNQEWKQRRIQPV (SEQ ID NO:27), wherein X 1 and X 2 are each a non-natural amino acid with an olefinic side chain, and wherein the internally cross-linked polypeptide is cell penetrant.
10. The internally cross-linked polypeptide of claim 9 , wherein X 1 and X 2 are each (S)-2-(4′-pentenyl) alanine (S5).
11. The internally cross-linked polypeptide of claim 10 , wherein the internally cross-linked polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 27.
12. A pharmaceutical composition comprising the internally cross-linked polypeptide of claim 11 , and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition of claim 12 , further comprising an inhibitor of EZH2 enzymatic activity.
14. The pharmaceutical composition of claim 13 , wherein the inhibitor of EZH2 enzymatic activity is GSK126.
15. A method of treating an EZH2-overexpressing or EZH2-dependent cancer in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the internally cross-linked polypeptide of claim 10 .
16. The method of claim 15 , further comprising administering to the human subject an inhibitor of EZH2 enzymatic activity.
17. The method of claim 16 , wherein the inhibitor of EZH2 enzymatic activity is GSK126.
18. The method of claim 15 , wherein the cancer is a leukemia, a breast cancer, a prostate cancer, a sarcoma, or a neuroblastoma.
19. A method of treating an EZH2-overexpressing or EZH2-dependent cancer in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the pharmaceutical composition of claim 12 .
20. The method of claim 19 , further comprising administering to the human subject an inhibitor of EZH2 enzymatic activity.
21. The method of claim 20 , wherein the inhibitor of EZH2 enzymatic activity is GSK126.
22. The method of claim 19 , wherein the cancer is a leukemia, a breast cancer, a prostate cancer, a sarcoma, or a neuroblastoma.
23. An internally cross-linked polypeptide that inhibits the interaction between Enhancer of Zeste Homolog 2 (EZH2) and Embryonic Ectoderm Development (EED), the internally cross-linked polypeptide comprising the amino acid sequence FSSNRX 1 KILX 2 RTX 3 ILNX 4 EWKQRRIQPV (SEQ ID NO: 56), wherein X 1 , X 2 , X 3 , and X 4 are each a non-natural amino acid with an olefinic side chain, and wherein the internally cross-linked polypeptide is cell penetrant.
24. The internally cross-linked polypeptide of claim 23 , wherein X 1 , X 2 , X 3 , and X 4 are each (S)-2-(4′-pentenyl) alanine (S5).
25. The internally cross-linked polypeptide of claim 23 , wherein the internally cross-linked polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 56.
26. A pharmaceutical composition comprising the internally cross-linked polypeptide of claim 25 and a pharmaceutically acceptable carrier.
27. The pharmaceutical composition of claim 26 , further comprising an inhibitor of EZH2 enzymatic activity.
28. The pharmaceutical composition of claim 27 , wherein the inhibitor of EZH2 enzymatic activity is GSK126.
29. A method of treating an EZH2-overexpressing or EZH2-dependent cancer in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the internally cross-linked polypeptide of claim 23 .
30. The method of claim 29 , further comprising administering to the human subject an inhibitor of EZH2 enzymatic activity.
31. The method of claim 30 , wherein the inhibitor of EZH2enzymatic activity is GSK126.
32. An internally cross-linked polypeptide that inhibits the interaction between Enhancer of Zeste Homolog 2 (EZH2) and Embryonic Ectoderm Development (EED), the internally cross-linked polypeptide comprising an amino acid sequence set forth in FSSNRX 1 KILX 2 RTEILNQEWKQRRIQPV (SEQ ID NO:26), except that one or more amino acids at positions 2, 3, 9, 13, 14, 17, 21 or 23 of SEQ ID NO: 26 are substituted, and wherein X 1 , and X 2 , are each a non-natural amino acid with an olefinic side chain, and wherein the internally cross-linked polypeptide is cell penetrant.
33. The internally cross-linked polypeptide of claim 32 , wherein the amino acids at positions 13 and 17, are each substituted with a non-natural amino acid with an olefinic side chain.
34. The internally cross-linked polypeptide of claim 32 , wherein the internally cross-linked polypeptide consists of an amino acid sequence set forth in SEQ ID NO:26, but with 1 to 6 amino acid substitutions at positions selected from the group consisting of positions: 2, 3, 9, 13, 14, 17, 21, and 23, of SEQ ID NO: 26.
35. The internally cross-linked polypeptide of claim 32 , wherein the internally cross-linked polypeptide comprises an amino acid sequence set forth in SEQ ID NO: 26 but with 1 to 4 amino acid substitutions at positions 2, 3, 9, 13, 14, 17, 21 or 23.
36. The internally cross-linked polypeptide of claim 32 , wherein the internally cross-linked polypeptide comprises an amino acid sequence set forth in SEQ ID NO: 26 but with 1 amino acid substitution at position 2, 3, 9, 13, 14, 17, 21 or 23.
37. The internally cross-linked polypeptide of claim 32 , wherein the non-natural amino acid is S5 [(S)-2-4′-pentenyl) alanine].
38. A pharmaceutical composition comprising the internally cross-linked polypeptide of claim 32 and a pharmaceutically acceptable carrier.
39. The pharmaceutical composition of claim 38 , further comprising an inhibitor of EZH2 enzymatic activity.
40. The pharmaceutical composition of claim 39 , wherein the inhibitor of EZH2 enzymatic activity is GSK126.
41. A method of treating an EZH2-overexpressing or EZH2-dependent cancer in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the internally cross-linked polypeptide of claim 32 .
42. The method of claim 41 , further comprising administering to the human subject an inhibitor of EZH2 enzymatic activity.
43. The method of claim 42 , wherein the inhibitor of EZH2 enzymatic activity is GSK126.