IP Library › Granted Patent US 12,358,960
Granted Patent B2
US 12,358,960 · App. 17/600,468 · Granted Jul 15, 2025

Selective targeting of ubiquitin- and ubiquitin-like E1-activating enzymes by structurally-stabilized peptides

Inventors: Loren D. Walensky (Newton, MA); Ann Morgan Cathcart (Cambridge, MA); Gregory H. Bird (Pelham, NH)
Assignee: Dana-Farber Cancer Institute, Inc.
C07K14/4703A61K38/00
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Quick Facts
Patent No.
US 12,358,960
App. No.
17/600,468
Granted
Jul 15, 2025
Kind
B2
Abstract

This disclosure features structurally-stabilized and/or warhead-bearing structurally stabilized peptide inhibitors for targeting ubiquitin activating enzymes (E1). Also disclosed are methods of using such structurally-stabilized and warhead-bearing structurally stabilized peptides in the treatment of E1-expressing or -dependent cancers or diseases. Also provided are combination therapies comprising such structurally-stabilized and/or warhead-bearing structurally stabilized peptide for the treatment of E1-expressing or -dependent diseases.

Claims (30)

1. A peptide or a salt thereof comprising the amino acid sequence of SEQ ID NO:132 with 0 to 3 amino acid substitutions, wherein the amino acid substitutions, if present, are not at positions 5 and 12 of SEQ ID NO:132, wherein positions 5 and 12 of SEQ ID NO: 132 are internally cross-linked, wherein (a) position 5 of SEQ ID NO:132 is S-pentenyl alanine and position 12 of SEQ ID NO: 132 is R-octenyl alanine, or (b) position 5 of SEQ ID NO: 132 is R-octenyl alanine and position 12 of SEQ ID NO: 132 is S-pentenyl alanine, and wherein the peptide or the salt thereof inhibits a human E1-mediated thioester transfer to a human E2.

2. The peptide or the salt thereof of claim 1 , wherein the peptide or the salt thereof comprises the amino acid sequence of SEQ ID NO:132 with 1 to 3 amino acid substitutions.

3. The peptide or the salt thereof of claim 2 , wherein the peptide or the salt thereof is 17 to 25 amino acids in length.

4. The peptide or the salt thereof of claim 2 , wherein the peptide or the salt thereof is 17 amino acids in length.

5. The peptide or the salt thereof of claim 2 , wherein the 1 to 3 amino acid substitutions are not at any of positions 7, 9, 10, 13, and 16 of SEQ ID NO:132.

6. The peptide or the salt thereof of claim 5 , wherein the 1 to 3 amino acid substitutions are selected from: alanine at one or more of positions 1, 2, 3, 4, 6, 8, 11, 14, 15, and 17 of SEQ ID NO: 132, or glutamic acid at one or both of positions 6 and 8 of SEQ ID NO: 132.

7. The peptide or the salt thereof of claim 6 , wherein the peptide or the salt thereof is 17 to 25 amino acids in length.

8. The peptide or the salt thereof of claim 2 , wherein the 1 to 3 amino acid substitutions are not at any of positions 7, 9, 10, 13, 15, and 16 of SEQ ID NO:132.

9. The peptide or the salt thereof of claim 8 , wherein the 1 to 3 amino acid substitutions are selected from: alanine at one or more of positions 1, 2, 3, 4, 6, 8, 11, 14, and 17 of SEQ ID NO: 132, or glutamic acid at one or both of positions 6 and 8 of SEQ ID NO:132.

10. The peptide or the salt thereof of claim 9 , wherein the peptide or the salt thereof is 17 to 25 amino acids in length.

11. The peptide or the salt thereof of claim 1 , wherein the peptide or the salt thereof comprises the amino acid sequence of SEQ ID NO:132 with 1 amino acid substitution.

12. The peptide or the salt thereof of claim 11 , wherein the 1 amino acid substitution is not at any of positions 7, 9, 10, 13, and 16 of SEQ ID NO: 132.

13. The peptide or the salt thereof of claim 11 , wherein the 1 amino acid substitution is not at any of positions 7, 9, 10, 13, 15, and 16 of SEQ ID NO: 132.

14. The peptide or the salt thereof of claim 11 , wherein the 1 amino acid substitution is selected from: alanine at one of positions 1, 2, 3, 4, 6, 8, 11, 14, 15, and 17 of SEQ ID NO: 132, or glutamic acid at one of positions 6 and 8 of SEQ ID NO:132.

15. The peptide or the salt thereof of claim 11 , wherein the peptide or the salt thereof is 17 to 25 amino acids in length.

16. A pharmaceutical composition comprising the peptide or the salt thereof of claim 1 , and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising the peptide or the salt thereof of claim 11 , and a pharmaceutically acceptable carrier.

18. A peptide or a salt thereof comprising the amino acid sequence of SEQ ID NO:132, wherein position 5 of SEQ ID NO:132 is S-pentenyl alanine and position 12 of SEQ ID NO:132 is R-octenyl alanine, and wherein position 5 of SEQ ID NO:132 is cross-linked to position 12 of SEQ ID NO:132.

19. The peptide or the salt thereof of claim 18 , wherein the peptide or the salt thereof consists of the sequence of SEQ ID NO: 132, wherein position 5 of SEQ ID NO: 132 is S-pentenyl alanine and position 12 of SEQ ID NO:132 is R-octenyl alanine, and wherein position 5 of SEQ ID NO: 132 is cross-linked to position 12 of SEQ ID NO: 132.

20. The peptide or the salt thereof of claim 18 , wherein the peptide or the salt thereof is 17 to 25 amino acids in length.

21. A pharmaceutical composition comprising the peptide or the salt thereof of claim 18 , and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising the peptide or the salt thereof of claim 19 , and a pharmaceutically acceptable carrier.

23. A peptide or a salt thereof comprising the amino acid sequence of SEQ ID NO: 132, wherein position 5 of SEQ ID NO:132 is R-octenyl alanine and position 12 of SEQ ID NO: 132 is S-pentenyl alanine, and wherein position 5 of SEQ ID NO:132 is cross-linked to position 12 of SEQ ID NO:132.

24. The peptide or the salt thereof of claim 23 , wherein the peptide or the salt thereof consists of the amino acid sequence of SEQ ID NO: 132, wherein position 5 of SEQ ID NO: 132 is R-octenyl alanine and position 12 of SEQ ID NO:132 is S-pentenyl alanine, and wherein position 5 of SEQ ID NO:132 is cross-linked to position 12 of SEQ ID NO: 132.

25. The peptide or the salt thereof of claim 23 , wherein the peptide or the salt thereof is 17 to 25 amino acids in length.

26. A pharmaceutical composition comprising the peptide or the salt thereof of claim 23 , and a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising the peptide or the salt thereof of claim 24 , and a pharmaceutically acceptable carrier.

28. A method of making a structurally stabilized peptide, the method comprising:

(i) providing a peptide comprising the amino acid sequence of SEQ ID NO: 132 with 0 to 3 amino acid substitutions, wherein the amino acid substitutions, if present, are not at positions 5 and 12 of SEQ ID NO:132, wherein (a) position 5 of SEQ ID NO: 132 is S-pentenyl alanine and position 12 of SEQ ID NO:132 is R-octenyl alanine, or (b) position 5 of SEQ ID NO:132 is R-octenyl alanine and position 12 of SEQ ID NO: 132 is S-pentenyl alanine, wherein the peptide inhibits a human E1-mediated thioester transfer to a human E2; and

(ii) cross-linking the amino acids at positions 5 and 12 of SEQ ID NO:132.

Assignments (2)
CONFIRMATORY LICENSE Recorded Dec 13, 2023
From: DANA-FARBER CANCER INST
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065989/0649 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2021
From: WALENSKY, LOREN D.; CATHCART, ANN MORGAN; BIRD, GREGORY H.
To: DANA-FARBER CANCER INSTITUTE, INC.
Reel/Frame 057708/0633 →
Continuity (2)
Provisional Application 62835721 · Apr 18, 2019
Related Publication 20220169688A1 · Jun 2, 2022
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