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ACS Chem Biol. 2014 Sep 19;9(9):1962-8. doi: 10.1021/cb500340w. Epub 2014 Jul 23.

Designed BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells.

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1
Department of Biology, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.

Abstract

Mcl-1 is overexpressed in many cancers and can confer resistance to cell-death signaling in refractory disease. Molecules that specifically inhibit Mcl-1 hold potential for diagnosing and disrupting Mcl-1-dependent cell survival. We selected three peptides from a yeast-surface display library that showed moderate specificity and affinity for binding to Mcl-1 over Bfl-1, Bcl-xL, Bcl-2, and Bcl-w. Specificity for Mcl-1 was improved by introducing threonine at peptide position 2e. The most specific peptide, MS1, bound Mcl-1 with 40-fold or greater specificity over four other human Bcl-2 paralogs. In BH3 profiling assays, MS1 caused depolarization in several human Mcl-1-dependent cell lines with EC50 values of ∼3 μM, contrasted with EC50 values of >100 μM for Bcl-2-, Bcl-xL-, or Bfl-1-dependent cell lines. MS1 is at least 30-fold more potent in this assay than the previously used Mcl-1 targeting reagent NoxaA BH3. These peptides can be used to detect Mcl-1 dependency in cells and provide leads for developing Mcl-1 targeting therapeutics.

PMID:
25052212
PMCID:
PMC4168798
DOI:
10.1021/cb500340w
[Indexed for MEDLINE]
Free PMC Article

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