Peptidomimetic macrocycles

• US 8,859,723 B2
• Filed: 08/13/2011
• Issued: 10/14/2014
• Est. Priority Date: 08/13/2010
• Status: Active Grant

• Current Assignee: Aileron Therapeutics Inc.
• Original Assignee: Aileron Therapeutics Inc.
• Inventors: Guerlavais, Vincent, Kawahata, Noriyuki
• Primary Examiner(s): Garcia, Marcela M Cordero
• Assistant Examiner(s): Coffa, Sergio
• Application Number:
  US13/816,880
• Publication Number:
  US 20130210743A1
• Time in Patent Office: 1,158 Days
• US Class Current: 530/321
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 14/4746 p53
• CPC Class Codes: C07K 7/56 the cyclisation not occurring through 2,4-diamino-butanoic acid
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

The present invention provides novel 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 60% identical to an amino acid sequence of SEQ ID NO. 689.

2. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 80% identical to an amino acid sequence of SEQ ID NO. 689.

3. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 90% identical to an amino acid sequence of SEQ ID NO. 689.

4. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 95% identical to an amino acid sequence of SEQ ID NO. 689.

5. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is SEQ ID NO. 689.

6. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises a helix.

7. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an α

-helix.

8. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an α

,α

-disubstituted amino acid.

9. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises a crosslinker linking the α

-positions of at least two amino acids.

10. The peptidomimetic macrocycle of claim 9, wherein at least one of said two amino acids is an α

,α

-disubstituted amino acid.

11. The peptidomimetic macrocycle of any one of claims 1-10, wherein the peptidomimetic macrocycle has the formula:

12. The peptidomimetic macrocycle of claim 11, wherein L does not include a thioether or a triazole.

13. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises a cross linker linking a backbone amino group of a first amino acid to a second amino acid within the peptidomimetic macrocycle.

14. The peptidomimetic macrocycle of claim 13, wherein the peptidomimetic macrocycle has the formula (IV) or (IVa):

15. The peptidomimetic macrocycle of claim 14, wherein L₁ and L₂ either alone or in combination do not include a thioether or a triazole.

16. The peptidomimetic macrocycle of claim 11, wherein L₁ and L₂ are independently alkylene, alkenylene or alkynylene.

17. The peptidomimetic macrocycle of claim 11, wherein L₁ and L₂ are independently C₃-C₁₀ alkylene or alkenylene.

18. The peptidomimetic macrocycle of claim 17, wherein L₁ and L₂ are independently C₃-C₆ alkylene or alkenylene.

19. The peptidomimetic macrocycle of claim 11, wherein R₁ and R₂ are H.

20. The peptidomimetic macrocycle of claim 11, wherein R₁ and R₂ are independently alkyl.

21. The peptidomimetic macrocycle of claim 11, wherein R₁ and R₂ are methyl.

22. A method of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle of any one of claims 1-10.

23. A method of modulating the activity of a p53 protein, a HDM2 protein, a HDMX protein, or a combination thereof, in a subject comprising administering to the subject a peptidomimetic macrocycle of any one of claims 1-10.

24. A method of antagonizing the interaction between a p53 protein and a HDM2 proteins, between a p53 protein and a HDMX protein, or a combination thereof, in a subject comprising administering to the subject a peptidomimetic macrocycle of any one of claims 1-10.