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.
Publication types
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Letter
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Cell Line / drug effects
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Cell Surface Display Techniques / methods
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Fluorescence Polarization
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Humans
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Membrane Proteins / chemistry
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Membrane Proteins / metabolism
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Minor Histocompatibility Antigens
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Molecular Targeted Therapy / methods*
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism*
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Peptides / chemistry*
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Peptides / metabolism*
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Peptides / pharmacology
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Threonine / chemistry
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Threonine / metabolism
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bcl-X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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BCL2-related protein A1
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BCL2L1 protein, human
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BCL2L11 protein, human
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BCL2L2 protein, human
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Bax protein (53-86)
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Bcl-2-Like Protein 11
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MCL1 protein, human
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Membrane Proteins
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Minor Histocompatibility Antigens
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Myeloid Cell Leukemia Sequence 1 Protein
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Peptide Fragments
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Peptides
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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bcl-X Protein
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Threonine