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1. WO2020112868 - POLYTHÉRAPIE AYANT RECOURS À DES MACROCYCLES PEPTIDOMIMÉTIQUES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]
CLAIMS

WHAT IS CLAIMED IS:

1. A method of treating a condition in a subject in need thereof, comprising administering to the subject a combination therapy comprising a therapeutically-effective amount of a peptidomimetic macrocycle and a therapeutically-effective amount of paclitaxel, wherein the combination therapy has a combination index of less than 1.

2. The method of claim 1, wherein the combination therapy has a combination index of less than 0.9.

3. The method of claim 1, wherein the combination therapy has a combination index of about 0.8 to about 0.9.

4. The method of claim 1, wherein the combination index is calculated from a half maximal inhibitory concentration (IC50).

5. The method of claim 1, wherein the combination index is calculated from an IC75 value.

6. The method of claim 1, wherein the combination index is calculated from an in vitro cell proliferation assay.

7. The method of claim 1, wherein the combination index is calculated from an in vivo animal study.

8. The method of claim 1, wherein the condition is cancer.

9. The method of claim 8, wherein the cancer expresses wild type p53.

10. The method of claim 8, wherein the cancer is an advanced or metastatic solid tumor.

11. The method of claim 8, wherein the cancer is breast cancer.

12. The method of claim 8, wherein the cancer is estrogen receptor-positive breast cancer.

13. The method of claim 8, wherein the combination therapy delays tumor growth in the subject by at least 30 days.

14. The method of claim 8, wherein the combination therapy delays tumor growth in the subject by at least 20 days.

15. The method of claim 8, wherein the combination therapy delays tumor growth in the subject by at least 23.9 days.

16. The method of claim 8, wherein the combination therapy results in a percentage tumor growth delay that is at least about 50%.

17. The method of claim 8, wherein the combination therapy results in a percentage tumor growth delay that is at least about 60%.

18. The method of claim 8, wherein the percentage tumor growth delay (% TGD) is determined by the equation:


wherein:

T is a median time to endpoint (TTE) for a combination therapy group, and

C is a median TTE for a no combination therapy group.

19. The method of claim 1, wherein the peptidomimetic macrocycle inhibits HDMX.

20. The method of claim 1, wherein the peptidomimetic macrocycle inhibits HDM2.

21. The method of claim 1, wherein the peptidomimetic macrocycle stabilizes or increases a concentration of active p53 in the subject.

22. The method of claim 1, wherein the peptidomimetic macrocycle is a compound of Formula (I):


wherein:

- each A, C, D, and E is independently a natural or non-natural amino acid or an amino acid analog, and each terminal D and E independently optionally includes a capping group;

- each B is independently a natural or non-natural amino acid, an amino acid analog,


- each R1 and R2 is independently–H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl,

cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo–, or at least one of R1 and R2 forms a macrocycle-forming linker L’ connected to the alpha position of one of said D or E amino acids;

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

- each L and L’ is independently a macrocycle-forming linker of the formula–L1–L2–;

- each L1, L2, and L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene,

cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or [-R4-K-R4-]n, each being optionally substituted with R5;

- 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 R5 is independently halogen, alkyl, -OR6, -N(R6)2, -SR6, -SOR6, -SO2R6, -CO2R6, a fluorescent moiety, a radioisotope, or a therapeutic agent;

- each R6 is independently–H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl,

heterocycloalkyl, a fluorescent moiety, a radioisotope, or a therapeutic agent;

- each R7 is independently–H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;

- each R8 is independently–H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl,

cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;

- each v and w is independently an integer from 1-1000;

- u is an integer from 1-10;

- each x, y, and z is independently an integer from 0-10; and

- n is an integer from 1-5.

23. The method of claim 22, wherein v is 3-10.

24. The method of claim 22, wherein v is 3.

25. The method of claim 22, wherein w is 3-10.

26. The method of claim 22, wherein w is 6.

27. The method of claim 22, wherein x+y+z = 6.

28. The method of claim 22, wherein each L1 and L2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.

29. The method of claim 22, wherein each L1 and L2 is independently alkylene or alkenylene.

30. The method of claim 22, wherein each R1 and R2 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo–.

31. The method of claim 22, wherein each R1 and R2 is independently hydrogen.

32. The method of claim 22, wherein each Ri and R2 is independently alkyl.

33. The method of claim 22, wherein each Ri and R2 is independently methyl.

34. The method of claim 22, wherein u is 1.

35. The method of claim 22, wherein each E is Ser or Ala, or an analogue thereof.

36. The method of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence that is at least 60% identical to an amino acid sequence listed in Table 1, Table la, Table lb, Table lc, Table 2a, or Table 2b.

37. The method of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence that is at least 70% identical to an amino acid sequence listed in Table 1, Table la, Table lb, Table lc, Table 2a, or Table 2b.

38. The method of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence that is at least 80% identical to an amino acid sequence listed in Table 1, Table la, Table lb, Table lc, Table 2a, or Table 2b.

39. The method of claim 1, wherein the peptidomimetic macrocycle is at least 60% identical to SP-153, SP-303, SP-331, or SP-671.

40. The method of claim 1, wherein the paclitaxel is nanoparticle albumin-bound paclitaxel.

41. The method of claim 1, wherein the therapeutically-effective amount of the peptidomimetic macrocycle is about 0.01 mg/kg to about 1000 mg/kg per day.

42. The method of claim 1, wherein the therapeutically-effective amount of the peptidomimetic macrocycle is about 5 mg/kg per day.

43. The method of claim 1, wherein the therapeutically-effective amount of the paclitaxel is about 0.01 mg/kg to about 1000 mg/kg per day.

44. The method of claim 1, wherein the therapeutically-effective amount of the paclitaxel is about 15 mg/kg per day.

45. The method of claim 1, wherein the peptidomimetic macrocycle is administered by intravenous injection.

46. The method of claim 1, wherein the paclitaxel is administered by intravenous injection.

47. The method of claim 1, wherein the peptidomimetic macrocycle is administered weekly.

48. The method of claim 1, wherein the paclitaxel is administered weekly.

49. The method of claim 1, wherein the peptidomimetic macrocycle and the paclitaxel are administered simultaneously.

50. The method of claim 1, wherein the peptidomimetic macrocycle and the paclitaxel are administered sequentially.

51. The method of claim 1, wherein the peptidomimetic macrocycle and the paclitaxel are administered in the same composition.

52. The method of claim 1, wherein the peptidomimetic macrocycle and the paclitaxel are administered in separate compositions.

53. The method of claim 1, wherein the subject is murine.

54. The method of claim 1, wherein the subject is human.