Provided herein are peptidomimetic macrocycles containing amino acid sequences with at least two modified amino acids that form an intramolecular cross-link that can help to stabilize a secondary structure of the amino acid sequence. Suitable sequences for stabilization include those with homology t
Provided herein are peptidomimetic macrocycles containing amino acid sequences with at least two modified amino acids that form an intramolecular cross-link that can help to stabilize a secondary structure of the amino acid sequence. Suitable sequences for stabilization include those with homology to the p53 protein. These sequences can bind to the MDM2 and/or MDMX proteins. Also provided herein are methods of using such macrocycles for the treatment of diseases and disorders, such as cancers or other disorders characterized by a low level or low activity of a p53 protein or high level of activity of a MDM2 and/or MDMX protein.
대표청구항▼
1. A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-457, wherein the peptidomimetic macrocycle has the formula: or a pharmaceutically acceptable salt thereof, wherein: e
1. A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-457, wherein the peptidomimetic macrocycle has the formula: or a 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 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;each R2 is independently alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or 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 and 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, or heterocycloalkylene;each K is independently O, 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 hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;each R7 is independently hydrogen, 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 hydrogen, 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 is independently an integer from 1-1000;each 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; andeach n is independently an integer from 1-5; wherein a first C-terminal amino acid represented by E comprises a hydrophobic side chain, or when a w>1 a first or a second C-terminal amino acid represented by E comprises a hydrophobic side chain; and wherein the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof is not any of SEQ ID NOs: 728, 729, 737-740, 826, 828, 839-841, 857, 860, 864, 866, 868, 872, 881, 884, 897, 911, 914, 915, 920, 921, 923, 926-942, 960-973, 975-977, 1013-1016, 1069, 1070, 1076, 1088, 1089, 1095-1124, 1127-1132, 1136-1139, 1142, 1144, 1149-1151, 1172, 1173, 1178-1201, 1206-1210, 1214-1216, 1246-1252, 1256-1266, 1270, 1272-1278, 1284, 1288, 1289, 1295-1297, 1327, 1336-1339, 1344, 1345, 1360, 1362, 1363, 1369, 1378-1380, 1391, 1392, 1419-1421, 1430, 1431, 1434, 1436, 1438, 1451, 1453, 1473, 1478, or 1502. 2. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein a first C-terminal amino acid represented by E comprises a hydrophobic side chain. 3. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein w>1. 4. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 3, wherein a first C-terminal amino acid represented by E comprises a hydrophobic side chain. 5. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 4, wherein a second C-terminal amino acid represented by E comprises a hydrophobic side chain. 6. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 3, wherein a second C-terminal amino acid represented by E comprises a hydrophobic side chain. 7. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein w>3 and each of a two first amino acids represented by E is independently an amino acid comprising an uncharged side chain or an amino acid comprising a negatively charged side chain. 8. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein the hydrophobic side chain is a small hydrophobic side chain. 9. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein each R4 is independently alkylene, alkenylene, or alkynylene; and wherein each K is independently O, CO, CO2, or CONR3. 10. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof does not include a thioether. 11. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof comprises an amino acid sequence which is at least about 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-457. 12. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein each L1 and L2 and L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R5. 13. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein each L1 and L2 and L3 is independently alkylene or alkenylene. 14. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein each L is independently alkylene, alkenylene, or alkynylene. 15. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 14, wherein each L is independently C3-C16 alkylene, alkenylene, or alkynylene. 16. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 15, wherein each L is independently C10-C14 alkylene, alkenylene, or alkynylene. 17. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein each R1 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; and each R2 is independently alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-. 18. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 17, wherein R1 is hydrogen. 19. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 17, wherein each R1 and R2 is independently alkyl. 20. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 19, wherein R1 and R2 are methyl. 21. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein x+y+z=6. 22. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein u is 1. 23. A pharmaceutical composition comprising the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1. 24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is a liquid composition. 25. A method of treating cancer in a subject comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1. 26. The method of claim 25, wherein the cancer is selected from the group consisting of head and neck cancer, melanoma, lung cancer, breast cancer, and glioma. 27. A method of modulating the activity of p53 and/or MDM2 and/or MDMX in a subject comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1. 28. A method of antagonizing an interaction between p53 and MDM2 proteins and/or between p53 and MDMX proteins in a subject comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1. 29. A method of preparing a composition comprising a peptidomimetic macrocycle of Formula (Ia): or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence which is 95% to 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-457, the method comprising treating a compound of Formula (II): or a pharmaceutically acceptable salt thereof,with a catalyst to result in the compound of Formula (Ia) or pharmaceutically acceptable salt thereof; wherein in the compound of Formula (Ia) or pharmaceutically acceptable salt thereof and in the compound of Formula (II) or pharmaceutically acceptable salt thereof: 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 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halogen; or forms a macrocycle-forming linker L′ connected to the alpha position of one of the D or E amino acids;each R2 is independently alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halogen; or forms a macrocycle-forming linker L′ connected to the alpha position of one of the 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′ is independently a macrocycle-forming linker of the formula -L1-L2-;each L1 and 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 and R4′ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, or heterocycloalkylene;each K is independently O, 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 hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;each R7 is independently hydrogen, 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 hydrogen, 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 is independently an integer from 1-1000;each 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;each n is independently an integer from 1-5;each o is independently an integer from 1 to 15;each p is independently an integer from 1 to 15;(E) represents a trans double bond or an E-double bond; andone or more of A, B, and C has a side chain bearing a protecting group; wherein a first C-terminal amino acid represented by E comprises a hydrophobic side chain, or when a w>1 a first or a second C-terminal amino acid represented by E comprises a hydrophobic side chain; and wherein the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof is not any of SEQ ID NOs: 728, 729, 737-740, 826, 828, 839-841, 857, 860, 864, 866, 868, 872, 881, 884, 897, 911, 914, 915, 920, 921, 923, 926-942, 960-973, 975-977, 1013-1016, 1069, 1070, 1076, 1088, 1089, 1095-1124, 1127-1132, 1136-1139, 1142, 1144, 1149-1151, 1172, 1173, 1178-1201, 1206-1210, 1214-1216, 1246-1252, 1256-1266, 1270, 1272-1278, 1284, 1288, 1289, 1295-1297, 1327, 1336-1339, 1344, 1345, 1360, 1362, 1363, 1369, 1378-1380, 1391, 1392, 1419-1421, 1430, 1431, 1434, 1436, 1438, 1451, 1453, 1473, 1478 or 1502. 30. The method of claim 29, wherein the protecting group is a nitrogen atom protecting group. 31. The method of claim 29, wherein the protecting group is a Boc group. 32. The method of claim 30, wherein the side chain bearing the protecting group comprises a protected indole. 33. The method of claim 32, wherein the protecting group is borne on the side chain of a tryptophan (W) that is protected by the protecting group on its indole nitrogen. 34. The method of claim 33, wherein the protecting group is borne on the side chain of a tryptophan (W) that is protected on its indole nitrogen by a Boc group. 35. The method of claim 29, wherein after the step of treating the compound of Formula (II) or pharmaceutically acceptable salt thereof with the catalyst, the compound of Formula (Ia) or pharmaceutically acceptable salt thereof is obtained in an amount equal or higher than an amount obtained of a corresponding compound or pharmaceutically acceptable salt thereof which is a Z isomer. 36. The method of claim 35, wherein after the contacting the compound of Formula (II) or pharmaceutically acceptable salt thereof with the catalyst, the compound of Formula (Ia) or pharmaceutically acceptable salt thereof is obtained in an amount that is 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold higher than an amount obtained of the corresponding compound or pharmaceutically acceptable salt thereof which is the Z isomer. 37. The method of claim 29, wherein the catalyst is a ruthenium catalyst. 38. The method of claim 29, further comprising the step of treating the compound of Formula (Ia) or pharmaceutically acceptable salt thereof with a reducing agent or an oxidizing agent. 39. The method of claim 29, wherein the compound of Formula (II) or pharmaceutically acceptable salt thereof is attached to a solid support. 40. The method of claim 29, wherein the compound of Formula (II) or pharmaceutically acceptable salt thereof is not attached to a solid support. 41. The method of claim 29, further comprising removing the protecting group from the compound of Formula (Ia) or pharmaceutically acceptable salt thereof. 42. The method of claim 29, wherein the treating is conducted at a temperature ranging from about 20° C. to about 80° C. 43. The method of claim 29, wherein the peptidomimetic macrocycle of Formula (Ia) or pharmaceutically acceptable salt thereof comprises an α-helix. 44. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein each L is independently alkenylene. 45. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein w is 3-10. 46. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 45, wherein w is 3-6. 47. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 45, wherein w is 6-10. 48. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 45, wherein w is 6. 49. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 45, wherein w is 3. 50. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein v is 1-10. 51. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 50, wherein v is 3-10. 52. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 51, wherein v is 3-5. 53. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 52, wherein v is 3. 54. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 53, wherein [D]v is Leu1-Thr2-Xaa, wherein Xaa is independently an amino acid. 55. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein each w is independently 1-10 and v is 3. 56. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein each v is independently 1-10 and w is 3. 57. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein each v is independently 1-10 and w is 6. 58. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein v is 3 and w is 3. 59. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein v is 3 and w is 6. 60. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 21, wherein each w is independently 1-10 and v is 3. 61. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 21, wherein each v is independently 1-10 and w is 3. 62. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 21, wherein each v is independently 1-10 and w is 6. 63. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 21, wherein v is 3 and w is 3. 64. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 21, wherein v is 3 and w is 6. 65. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 22, wherein each w is independently 1-10 and v is 3. 66. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 22, wherein each v is independently 1-10 and w is 3. 67. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 22, wherein each v is independently 1-10 and w is 6. 68. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 22, wherein v is 3 and w is 3. 69. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 22, wherein v is 3 and w is 6. 70. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein w is 3, v is 3, u is 1, and x+y+z is 6. 71. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, wherein w is 6, v is 3, u is 1, and x+y+z is 6.
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