Methods and compositions for specific modulation of MCL-1
First Claim
Patent Images
1. A peptide comprising an amino acid sequence selected from the group consisting of:
- LEVESATQLRXFGDXLNFRQKL (SEQ ID NO;
63),LEVESXTQLXRFGDKLNFRQL (SEQ ID NO;
64),LEVESXTQLXRFGDKLNF (SEQ ID NO;
65),LEVXSATXLRRFGDKLNFRQKL (SEQ ID NO;
66),LEVESATQLRRFGDKLXFRQXL (SEQ ID NO;
67), andLEVEXATQXRRFGDKLNFRQKL (SEQ ID NO;
68),wherein X is a non-natural amino acid containing an olefinic side chain, andwherein the peptide comprises a stabilized alpha-helix with the non-natural amino acids connected by a hydrocarbon staple.
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Abstract
A series of stapled BCL-2 family peptide helices were identified as able to target the survival protein MCL-I with high affinity and a subset with unprecedented selectivity. Agents and methods for selective pharmacologic neutralization of MCL-I are provided for drug discovery and therapeutic uses, including use in overcoming the apoptotic resistance of cancer and other diseases associated with impaired cell death.
14 Citations
21 Claims
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1. A peptide comprising an amino acid sequence selected from the group consisting of:
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LEVESATQLRXFGDXLNFRQKL (SEQ ID NO;
63),LEVESXTQLXRFGDKLNFRQL (SEQ ID NO;
64),LEVESXTQLXRFGDKLNF (SEQ ID NO;
65),LEVXSATXLRRFGDKLNFRQKL (SEQ ID NO;
66),LEVESATQLRRFGDKLXFRQXL (SEQ ID NO;
67), andLEVEXATQXRRFGDKLNFRQKL (SEQ ID NO;
68),wherein X is a non-natural amino acid containing an olefinic side chain, and wherein the peptide comprises a stabilized alpha-helix with the non-natural amino acids connected by a hydrocarbon staple. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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10. A peptide comprising an amino acid sequence that is at least 90% identical to LEVESATQLRRFGDKLNFRQKL (SEQ ID NO:
- 77), wherein the peptide comprises a stabilized alpha-helix with non-natural amino acids comprising a hydrocarbon staple between relative positions i and i+3, i and i+4, or i and i+7 of the peptide.
- View Dependent Claims (19, 20, 21)
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11. A peptide comprising the amino acid sequence:
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IWIXQELXRFGDKFNAYYAR (SEQ ID NO;
61)wherein X is a non-natural amino acid containing an olefinic side chain, and wherein the peptide comprises a stabilized alpha-helix with the non-natural amino acids connected by a hydrocarbon staple. - View Dependent Claims (12, 13, 14)
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15. A peptide comprising the amino acid sequence:
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VGQLLQXMGDXVYQQYRSLTR (SEQ ID NO;
70),wherein X is a non-natural amino acid containing an olefinic side chain, and wherein the peptide comprises a stabilized alpha-helix with the non-natural amino acids connected by a hydrocarbon staple. - View Dependent Claims (16, 17, 18)
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Specification