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

TitleDesigned BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells.
Publication TypeJournal Article
Year of Publication2014
AuthorsFoight GWink, Ryan JA, Gullá SV, Letai A, Keating AE
JournalACS Chem Biol
Date Published2014 Sep 19
KeywordsApoptosis Regulatory Proteins, bcl-X Protein, Cell Line, Cell Surface Display Techniques, Fluorescence Polarization, Humans, Membrane Proteins, Molecular Targeted Therapy, Myeloid Cell Leukemia Sequence 1 Protein, Peptide Fragments, Peptides, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Threonine

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.

Alternate JournalACS Chem. Biol.
PubMed ID25052212
PubMed Central IDPMC4168798
Grant ListP01-CA129980 / CA / NCI NIH HHS / United States
P50-GM068762 / GM / NIGMS NIH HHS / United States
R01-GM084181 / GM / NIGMS NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States