Peptidomimetic macrocycles and uses thereof

• US 10,471,120 B2
• Filed: 09/24/2015
• Issued: 11/12/2019
• Est. Priority Date: 09/24/2014
• Status: Active Grant

• Current Assignee: Aileron Therapeutics Inc.
• Original Assignee: Aileron Therapeutics Inc.
• Inventors: Chen, Hubert, Annis, David Allen, Chang, Yong, Aivado, Manuel, Olson, Karen, Viau, Chris J.
• Primary Examiner(s): Yang, Kaipeen E
• Application Number:
  US14/864,801
• Publication Number:
  US 20160193283A1
• Time in Patent Office: 1,510 Days
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers

Abstract

Methods for treating solid tumor, determined to lack a p53 deactivation mutation, in a subject are provided. Also provided are peptidomimetic macrocycles for use in treatment of a solid tumor, determined to lack a p53 deactivation mutation, in a subject.

Claims

1. A method of treating a solid tumor in a human subject in need thereof, wherein the method comprises administering to the human subject 0.5-10 mg of a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof per kilogram body weight of the human subject at least once a week, wherein the solid tumor (i) has a wild type p53 and (ii) is breast cancer, colorectal cancer, endometrial cancer, liver cancer, lung cancer, nerve cancer, multiple myeloma, ovarian cancer, skin cancer, submandibular adenocarcinoma, leiomyosarcoma or thymoma;

and wherein the peptidomimetic macrocycle (i) binds to a protein in a p53 pathway of the human subject, (ii) comprises an amino acid sequence in any of SEQ ID NOs;

10-692 and 1500, and (iii) has a Formula (I);

3. The method of claim 1, wherein L has a formula -L₁-L₂-, wherein each L₁ and L₂ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or [R₄-K-R₄]_n, each being optionally substituted with R₅,

wherein:

each R₄ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is independently O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₃ independently is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heteroaryl, optionally substituted with R₅; and

n is independently an integer from 1-5.

4. The method of claim 3, wherein each L₁ and L₂ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R₅.

5. The method of claim 1, wherein the amount of the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof administered is about 0.5-5 mg per kilogram body weight of the human subject.

6. The method of claim 1, wherein the amount of the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof administered is about 0.64 mg per kilogram body weight of the human subject, about 1.28 mg per kilogram body weight of the human subject, about 3.56 mg per kilogram body weight of the human subject, or about 7.12 mg per kilogram body weight of the human subject.

7. The method of claim 1, wherein the amount of the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof administered is about 0.64 mg per kilogram body weight of the human subject, about 1.25 mg per kilogram body weight of the human subject, about 2.5 mg per kilogram body weight of the human subject, about 5.0 mg per kilogram body weight of the human subject, or 10.0 mg per kilogram body weight of the human subject.

8. The method of claim 1, wherein the administering is over a period of 0.25-2.0 h.

9. The method of claim 1, wherein the solid tumor is selected from a group consisting of breast cancer, liver cancer, lung cancer, skin cancer, ovarian cancer, leiomyosarcoma, and thymoma.

10. The method of claim 1, wherein the administering is intravenous.

11. The method of claim 1, wherein w is 3, 4, 5, or 6.

12. The method of claim 1, wherein v is an integer from 2 to 5.

13. The method of claim 1, wherein each R₁ and R₂ is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-.

14. The method of claim 1, further comprising:

prior to the administering, determining that the solid tumor in the human subject has the wild type p53.

15. The method of claim 14, wherein the determining that the solid tumor in the human subject has the wild type p53 comprises RNA array based testing.

16. The method of claim 14, wherein the determining that the solid tumor in the human subject has the wild type p53 comprises RNA analysis.

17. The method of claim 14, wherein the determining that the solid tumor in the human subject has the wild type p53 comprises polymerase chain reaction (PCR).

18. The method of claim 14, wherein the determining that the solid tumor in the human subject has the wild type p53 comprises DNA sequencing.

19. The method of claim 14, wherein the determining is performed up to about 3 years prior to the administering.

20. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

32.

21. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

466.

22. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

79.

23. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

286.

24. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

330.

25. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

340.

26. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

553.

27. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

561.

2. A method of treating a solid tumor in a human subject in need thereof, wherein the method comprises administering to the human subject 0.32-10 mg of a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof per kilogram body weight of the human subject at least twice a week;

wherein the solid tumor (i) has a wild type p53 and (ii) is breast cancer, colorectal cancer, endometrial cancer, liver cancer, lung cancer, nerve cancer, multiple myeloma, ovarian cancer, skin cancer, submandibular adenocarcinoma, leiomyosarcoma or thymoma; and

wherein the peptidomimetic macrocycle (i) binds to a protein in a p53 pathway of the human subject, (ii) comprises an amino acid sequence in any of SEQ ID NOs;

10-692 and 1500, and (iii) has a Formula (I);

28. The method of claim 2, wherein L has a formula -L₁-L₂-, wherein each L₁ and L₂ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or [R₄-K-R₄]_n, each being optionally substituted with R₅,

wherein:

each R₄ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is independently O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₃ independently is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heteroaryl, optionally substituted with R₅;

and

n is independently an integer from 1-5.

29. The method of claim 28, wherein each L₁ and L₂ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R₅.

30. The method of claim 2, wherein the amount of the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof administered is about 0.5-5 mg per kilogram body weight of the human subject.

31. The method of claim 2, wherein the amount of the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof administered is about 0.64 mg per kilogram body weight of the human subject, about 1.28 mg per kilogram body weight of the human subject, about 3.56 mg per kilogram body weight of the human subject, or about 7.12 mg per kilogram body weight of the human subject.

32. The method of claim 2, wherein the amount of the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof administered is about 0.64 mg per kilogram body weight of the human subject, about 1.25 mg per kilogram body weight of the human subject, about 2.5 mg per kilogram body weight of the human subject, about 5.0 mg per kilogram body weight of the human subject, or 10.0 mg per kilogram body weight of the human subject, wherein the administering is two times a week.

33. The method of claim 2, wherein the administering is over a period of 0.25-2.0 h.

34. The method of claim 2, wherein the solid tumor is selected from a group consisting of breast cancer, liver cancer, lung cancer, skin cancer, ovarian cancer, leiomyosarcoma, and thymoma.

35. The method of claim 2, wherein the administering is intravenous.

36. The method of claim 2, wherein w is 3, 4, 5, or 6.

37. The method of claim 2, wherein v is an integer from 2 to 5.

38. The method of claim 2, wherein each R₁ and R₂ is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-.

39. The method of claim 2, further comprising:

prior to the administering, determining that the solid tumor in the human subject has the wild type p53.

40. The method of claim 39, wherein the determining that the solid tumor in the human subject has the wild type p53 comprises RNA array based testing.

41. The method of claim 39, wherein the determining that the solid tumor in the human subject has the wild type p53 comprises RNA analysis.

42. The method of claim 39, wherein the determining that the solid tumor in the human subject has the wild type p53 comprises polymerase chain reaction (PCR).

43. The method of claim 39, wherein the determining that the solid tumor in the human subject has the wild type p53 comprises DNA sequencing.

44. The method of claim 39, wherein the determining is performed up to about 3 years prior to the administering.

45. The method of claim 2, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

32.

46. The method of claim 2, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

466.

47. The method of claim 2, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

79.

48. The method of claim 2, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

286.

49. The method of claim 2, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

330.

50. The method of claim 2, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

340.

51. The method of claim 2, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

553.

52. The method of claim 2, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence of SEQ ID NO:

561.

53. The method of claim 2, wherein the amount of the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof administered is about 0.64 mg per kilogram body weight of the human subject, about 1.25 mg per kilogram body weight of the human subject, about 2.5 mg per kilogram body weight of the human subject, or about 5.0 mg per kilogram body weight of the human subject, wherein the administering is on days 1, 4, 8, and 11 of a 21-day cycle.