Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles

• US 8,987,414 B2
• Filed: 02/14/2013
• Issued: 03/24/2015
• Est. Priority Date: 02/15/2012
• Status: Active Grant

• Current Assignee: Aileron Therapeutics Inc.
• Original Assignee: Aileron Therapeutics Inc.
• Inventors: Guerlavais, Vincent, Conlee, Christopher R., Lentini, Scott Paul
• Primary Examiner(s): Cordero Garcia, Marcela M
• Assistant Examiner(s): Coffa, Sergio
• Application Number:
  US13/767,857
• Publication Number:
  US 20130210745A1
• Time in Patent Office: 768 Days
• Field of Search: None
• US Class Current: 530/321
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/56 the cyclisation not occurring through 2,4-diamino-butanoic acid

Abstract

Provided herein are peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.

Claims

1. A peptidomimetic macrocycle comprising an amino acid sequence which is at least 90% identical to an amino acid sequence of SEQ ID NO. 455, wherein the peptidomimetic macrocycle has the formula:

2. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, which has improved binding affinity to MDM2 or MDMX relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2.

3. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, which has a reduced ratio of binding affinities to MDMX versus MDM2 relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2.

4. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, which has improved in vitro anti-tumor efficacy against p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2.

5. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, which shows improved in vitro induction of apoptosis in p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2.

6. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, which has an improved in vitro anti-tumor efficacy ratio for p53 positive versus p53 negative or mutant tumor cell lines relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2.

7. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, which has improved in vivo anti-tumor efficacy against p53 positive tumors relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2.

8. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, which has improved in vivo induction of apoptosis in p53 positive tumors relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2.

9. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, which has improved cell permeability relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2.

10. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, which has improved solubility relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2.

11. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein each E is independently an amino acid selected from Ala (alanine), D-Ala (D-alanine), Aib (α

-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine).

12. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein [D]_v is -Leu₁-Thr₂-Phe₃.

13. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein w is 3-10.

14. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 13, wherein w is 3-6.

15. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 13, wherein w is 6-10.

16. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 15, wherein w is 6.

17. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein v is 1-10.

18. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 17, wherein v is 2-10.

19. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 18, wherein v is 2-5.

20. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 18, wherein v is 2.

21. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein each E is independently Ser or Ala or an analog of Ser or Ala.

22. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, comprising at least one amino acid which is an amino acid analog.

23. A method of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1.

24. A method of modulating the activity of p53 and/or MDM2 and/or MDMX in a subject comprising administering to the subject a peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1.

25. A method of antagonizing the interaction between p53 and MDM2 and/or between p53 and MDMX proteins in a subject comprising administering to the subject a peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1.

26. The peptidomimetic macrocycle of claim 1, which is at least 95% identical to an amino acid sequence of SEQ ID NO. 455, an isomer or pharmaceutically acceptable salt thereof.

27. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein v is an integer from 1-500.

28. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein v is an integer from 1-200.

29. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein v is an integer from 1-100.

30. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein v is an integer from 1-50.

31. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein v is an integer from 1-30.

32. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein the sum of x+y+z is 2, 3, or 6.

33. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein w is an integer from 3-500.

34. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein w is an integer from 3-200.

35. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein w is an integer from 3-100.

36. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein w is an integer from 3-50.

37. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1 or 32, wherein w is an integer from 3-30.

38. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1 or 31, wherein w is an integer from 3-20.

39. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claims 1 or 32, wherein v is an integer from 1-20.

40. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1, wherein u is an integer from 1-5.

41. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1 or 31, wherein u is an integer from 1-3.

42. The peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of claim 1 or 32, wherein u is an integer from 1-2.

43. The peptidomimetic macrocycle of claim 1, consisting of an amino acid sequence of SEQ ID NO. 455, an isomer or pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising the peptidomimetic macrocycle, isomer or pharmaceutically acceptable salt of any one of claims 1, 26, and 43.