METHODS AND COMPOSITIONS FOR SPECIFIC MODULATION OF MCL-1
First Claim
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1. A peptide that binds specifically to MCL-1 with at least a 2-fold, 5-fold, 10-fold, 15-fold, or 20-fold greater affinity than to MCL-1 than any other member of the human BCL-2 family wherein the peptide comprises a stabilized α
- -helix with non-natural amino acids comprising the staple located between relative positions i and i+3, i and I+4, or i and i+7 derived from a polypeptide sequence selected from the group consisting of an MCL-1 stabilized alpha-helix of BCL-2 family BH3 domain (SAHB) peptide, a NOXA SAHB polypeptide, a BOK SAHB peptide, a tailored BIM SAHB peptide, a BAK SAHB peptide, and a MULE SAHB peptide.
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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.
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2 Claims
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1. A peptide that binds specifically to MCL-1 with at least a 2-fold, 5-fold, 10-fold, 15-fold, or 20-fold greater affinity than to MCL-1 than any other member of the human BCL-2 family wherein the peptide comprises a stabilized α
- -helix with non-natural amino acids comprising the staple located between relative positions i and i+3, i and I+4, or i and i+7 derived from a polypeptide sequence selected from the group consisting of an MCL-1 stabilized alpha-helix of BCL-2 family BH3 domain (SAHB) peptide, a NOXA SAHB polypeptide, a BOK SAHB peptide, a tailored BIM SAHB peptide, a BAK SAHB peptide, and a MULE SAHB peptide.
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2-82. -82. (canceled)
Specification