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Kafe 바로가기국가/구분 | United States(US) Patent 등록 |
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국제특허분류(IPC7판) |
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출원번호 | US-0074794 (2016-03-18) |
등록번호 | US-10253067 (2019-04-09) |
발명자 / 주소 |
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출원인 / 주소 |
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대리인 / 주소 |
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인용정보 | 피인용 횟수 : 0 인용 특허 : 305 |
Methods for treating liquid cancer, determined to lack a p53 deactivation mutation, in a subject are provided. Also provided are peptidomimetic macrocycles for use in treatment of a liquid cancer, determined to lack a p53 deactivation mutation, in a subject.
1. A method of treating a liquid tumor in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof, wherein the peptidomimetic macrocycle or the pha
1. A method of treating a liquid tumor in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof binds to a protein in a p53 pathway of the human subject, wherein the liquid tumor has no p53 deactivating mutation, wherein the human subject is refractory to another treatment of the liquid tumor. 2. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof disrupts an interaction between a p53 protein and a MDM2 protein. 3. The method of claim 1, further comprising determining a lack of a p53 deactivating mutation in the liquid tumor prior to the administration. 4. The method of claim 3, wherein the determining the lack of the p53 deactivating mutation comprises confirming a presence of wild type p53 in the liquid tumor. 5. The method of claim 1, further comprising determining a presence of a p53 gain of function mutation in the liquid tumor. 6. The method of claim 1, wherein the therapeutically effective amount is about 0.5 to about 10 mg per kilogram body weight of the human subject. 7. The method of claim 1, wherein the liquid tumor is a liquid lymphoma. 8. The method of claim 1, wherein the liquid tumor is a leukemia. 9. The method of claim 1, wherein the liquid tumor is a myeloma. 10. The method of claim 1, wherein the liquid tumor is not a HPV positive cancer. 11. The method of claim 1, wherein the administration is intravenous. 12. The method of claim 3, wherein the lack of the p53 deactivation mutation in the liquid tumor is determined by DNA sequencing of the nucleic acid encoding the p53 protein. 13. The method of claim 3, wherein the lack of the p53 deactivation mutation in the liquid tumor is determined by RNA array based testing. 14. The method of claim 3, wherein the lack of the p53 deactivation mutation in the liquid tumor is determined by RNA analysis. 15. The method of claim 3, wherein the lack of the p53 deactivation mutation in the liquid tumor is determined by polymerase chain reaction. 16. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence which is at least about 60% identical to an amino acid sequence in any of Table 3, Table 3a, Table 3b, and Table 3c, wherein the peptidomimetic macrocycle has a Formula (I): wherein:each A, C, and D is independently an amino acid;each B is independently an amino acid, [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-]; each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);each R1 and R2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; orforms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;each R3 independently is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;each L and L′ is independently a macrocycle-forming linker;each L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, 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, 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;each v is independently an integer from 0-1000;each w is independently an integer from 3-1000;u is an integer from 1-10;each x, y and z is independently an integer from 0-10; andeach n is independently an integer from 1-5. 17. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof has a formula: wherein: each of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 is individually an amino acid, wherein at least three of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 are the same amino acid as the amino acid at the corresponding position of the sequence Phe3-X4-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12 (SEQ ID NO: 8), where each X4 and X11 is independently an amino acid;each D is independently an amino acid;each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; orforms 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;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;R7 is —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;R8 is —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; andw is an integer from 0-1000. 18. The method of claim 16, L has a formula-L1-L2-, wherein L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4-]n, each being optionally substituted with R5. 19. The method of claim 17, wherein Xaa5 is Glu or an amino acid analog thereof. 20. The method of claim 16, wherein each E is independently Ala (alanine), Ser (serine) or an analog thereof. 21. The method of claim 17, wherein [D]v is-Leu1-Thr2. 22. The method of claim 16, wherein is 3-10. 23. The method of claim 16, wherein w is 3-6. 24. The method of claim 16, wherein w is 6-10. 25. The method of claim 16, wherein w is 6. 26. The method of claim 16, wherein v is 1-10. 27. The method of claim 16, wherein v is 2-5. 28. The method of claim 18, wherein L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, or heterocycloarylene, each being optionally substituted with R5. 29. The method of claim 18, wherein L1 and L2 are independently alkylene or alkenylene. 30. The method of claim 16, wherein L is alkylene, alkenylene, or alkynylene. 31. The method of claim 16, wherein L is alkylene. 32. The method of claim 16, wherein L is C3-C16 alkylene. 33. The method of claim 16, wherein L is C10-C14 alkylene. 34. The method of claim 16, wherein R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-. 35. The method of claim 16, wherein both R1 and R2 are —H. 36. The method of claim 16, wherein each R1 and R2 is independently alkyl. 37. The method of claim 16, wherein both R1 and R2 are methyl. 38. The method of claim 16, wherein x+y+z=6. 39. The method of claim 16, wherein u is 1. 40. The method of claim 16, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises at least one amino acid which is an amino acid analog. 41. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 163): or a pharmaceutically acceptable salt thereof. 42. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 124): or a pharmaceutically acceptable salt thereof. 43. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 123): or a pharmaceutically acceptable salt thereof. 44. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 108): or a pharmaceutically acceptable salt thereof. 45. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 397): or a pharmaceutically acceptable salt thereof. 46. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 340): or a pharmaceutically acceptable salt thereof. 47. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 454): or a pharmaceutically acceptable salt thereof. 48. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 360): or a pharmaceutically acceptable salt thereof. 49. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 80): or a pharmaceutically acceptable salt thereof. 50. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 78): or a pharmaceutically acceptable salt thereof. 51. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 16): or a pharmaceutically acceptable salt thereof. 52. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 169): or a pharmaceutically acceptable salt thereof. 53. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 324): or a pharmaceutically acceptable salt thereof. 54. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 258): or a pharmaceutically acceptable salt thereof. 55. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 446): or a pharmaceutically acceptable salt thereof. 56. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 358): or a pharmaceutically acceptable salt thereof. 57. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 464): or a pharmaceutically acceptable salt thereof. 58. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 466): or a pharmaceutically acceptable salt thereof. 59. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 467): or a pharmaceutically acceptable salt thereof. 60. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 376): or a pharmaceutically acceptable salt thereof. 61. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 471): or a pharmaceutically acceptable salt thereof. 62. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 473): or a pharmaceutically acceptable salt thereof. 63. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 475): or a pharmaceutically acceptable salt thereof. 64. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 476): or a pharmaceutically acceptable salt thereof. 65. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 481): or a pharmaceutically acceptable salt thereof. 66. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 482): or a pharmaceutically acceptable salt thereof. 67. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 487): or a pharmaceutically acceptable salt thereof. 68. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 572): or a pharmaceutically acceptable salt thereof. 69. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 572): or a pharmaceutically acceptable salt thereof. 70. The method of claim 16, wherein the peptidomimetic macrocycle has formula (SEQ ID NO: 1500): or a pharmaceutically acceptable salt thereof. 71. The method of claim 16, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence which is at least about 70% identical to the amino acid sequence in any of Table 3, Table 3a, Table 3b, and Table 3c. 72. The method of claim 16, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence which is at least about 80% identical to the amino acid sequence in any of Table 3, Table 3a, Table 3b, and Table 3c. 73. The method of claim 16, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence which is at least about 90% identical to the amino acid sequence in any of Table 3, Table 3a, Table 3b, and Table 3c. 74. The method of claim 16, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof comprises an amino acid sequence which is at least about 95% identical to the amino acid sequence in any of Table 3, Table 3a, Table 3b, and Table 3c. 75. The method of claim 1, wherein the protein is MDM2. 76. The method of claim 1, wherein the protein is MDMX. 77. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof disrupts an interaction between p53 and MDMX. 78. The method of claim 1, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt thereof has a formula: wherein: each of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 is individually an amino acid, wherein at least three of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 are the same amino acid as the amino acid at the corresponding position of the sequence Phe3-X4-Glu5-Tyr6-Trp7-Ala8-Gln9-Leu10/Cba10-X11-Ala12 (SEQ ID NO: 9), where each X4 and X11 is independently an amino acid;each D is independently an amino acid;each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; orforms 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;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;R7 is —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;R8 is —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; andw is an integer from 0-1000. 79. The method of claim 1, wherein the peptidomimetic macrocycle comprises a amino acid sequence Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12, wherein Xaa3 is Phe or an analog thereof; Xaa4 and Xaa11 are independently a cross-linking amino acid;Xaa5 is Glu, His, or an analog thereof;Xaa6 is Tyr, or an analog thereof;Xaa7 is Trp, or an analog thereof;Xaa8 is Ala, or an analog thereof;Xaa9 is Gln, or an analog thereof;Xaa10 is Leu, Cba, or an analog thereof; andXaa12 is Ser, Ala or an analog thereof. 80. The method of claim 1, wherein the liquid tumor is peripheral T cell lymphoma. 81. The method of claim 1, wherein the liquid tumor is acute myeloid leukemia (AML). 82. The method of claim 1, wherein the liquid tumor is a myelodysplastic syndrome (MDS). 83. The method of claim 1, further comprising administering a therapeutically effective amount of at least one additional therapeutic agent to the human subject. 84. The method of claim 1, wherein the liquid cancer is selected from the group consisting of myelodysplastic syndrome, acute myeloid leukemia, multiple myeloma, neoplasm, chronic myeloproliferative disorder, myelofibrosis, thrombocythemia, and polycythemia vera.
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