Peptidomimetic macrocycles as modulators of MCL-1

• US 10,023,613 B2
• Filed: 09/08/2016
• Issued: 07/17/2018
• Est. Priority Date: 09/10/2015
• Status: Active Grant

• Current Assignee: Aileron Therapeutics Inc.
• Original Assignee: Aileron Therapeutics Inc.
• Inventors: Guerlavais, Vincent, Feyfant, Eric
• Primary Examiner(s): Ahmed, Hasan S
• Assistant Examiner(s): Yang, Kaipeen E
• Application Number:
  US15/259,947
• Publication Number:
  US 20170107252A1
• Time in Patent Office: 677 Days
• 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: C07K 14/4702 Regulators; Modulating activity
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

The disclosed peptidomimetic macrocycles modulate the activity of MCL-1. Myeloid cell leukemia 1 (MCL-1) is a protein that inhibits cell death. Peptidomimetic macrocycles, pharmaceutical compositions, and methods disclosed herein can be used for the treatment of disease in which MCL-1 is over-expressed, such as cancer. In particular, MCL-1-modulating peptidomimetic macrocycles disclosed herein can be applied in the setting of resistance to BCL-2 family inhibitors, which is often engendered by MCL-1 over-expression or hyper-activation.

Claims

1. A peptidomimetic macrocycle of Formula (Ic):

2. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises two crosslinks, wherein a first crosslink is of a first pair of amino acid residues, and a second crosslink is of a second pair of amino acid residues.

3. The peptidomimetic macrocycle of claim 2, wherein the first pair of amino acid residues and the second pair of amino acid residues do not share a common amino acid residue.

4. The peptidomimetic macrocycle of claim 2, wherein the first pair of amino acid residues and the second pair of amino acid residues share one common amino acid residue.

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

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

-helix.

7. The peptidomimetic macrocycle of claim 1, wherein v is an integer from 1 to 15.

8. The peptidomimetic macrocycle of claim 1, wherein L is

9. The peptidomimetic macrocycle of claim 1, wherein R¹ and R² are H.

10. The peptidomimetic macrocycle of claim 1, wherein R¹ and R² are methyl.

11. A pharmaceutical composition comprising a peptidomimetic macrocycle of claim 1 and a pharmaceutically-acceptable carrier.

12. A method of treating a disorder, the method comprising administering to a subject in need thereof a therapeutically-effective amount of the peptidomimetic macrocycle of claim 1.

13. The method of claim 12, wherein the disorder is a cancer.

14. The method of claim 13, wherein the cancer is resistant to a BCL-2 inhibitor therapy.

15. The peptidomimetic macrocycle of claim 1, wherein L is the formula -L¹-L²-, and L¹ and L² are independently alkylene, alkenylene, or alkynylene.

16. The peptidomimetic macrocycle of claim 1, wherein L is the formula -L¹-L²-, and L¹ and L² are independently C₃-C₁₀ alkylene or C₃-C₁₀ alkenylene.

17. The peptidomimetic macrocycle of claim 1, wherein L is the formula -L¹-L²-, and L¹ and L² are independently C₃-C₆ alkylene or C₃-C₆ alkenylene.