Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-038/12
C07K-005/00
C07K-007/00
C07K-016/00
C07K-017/00
A61K-038/00
A61P-035/00
C07K-007/56
출원번호
US-0767857
(2013-02-14)
등록번호
US-8987414
(2015-03-24)
발명자
/ 주소
Guerlavais, Vincent
Conlee, Christopher R.
Lentini, Scott Paul
출원인 / 주소
Aileron Therapeutics, Inc.
대리인 / 주소
Wilson Sonsini Goodrich & Rosati, P.C.
인용정보
피인용 횟수 :
18인용 특허 :
102
초록
Provided herein are peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.
대표청구항▼
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: an isomer or pharmaceutically acceptable salt thereof wherein:each A, C, D, and E is independently an
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: an isomer or pharmaceutically acceptable salt thereof wherein:each A, C, D, and E is independently an amino acid;each B is independently an amino acid, [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-]; 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 L and L′ is independently a macrocycle-forming linker of the formula each L1, L2 and L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, 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, cycloaryl, or heterocycloaryl, 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, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;v is an integer from 1-1000;w is an integer from 3-1000;u is an integer from 1-10;each x, y and z is independently an integer from 0-10; andn is an integer from 1-5. 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.
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