Abstract
The development of selective inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Such precisely tailored compounds would serve as molecular probes and targeted therapies to study and treat human diseases driven by specific anti-apoptotic blockades. In particular, MCL-1 has emerged as a major resistance factor in human cancer. By screening a library of stabilized alpha-helix of BCL-2 domains (SAHBs), we determined that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity. MCL-1 SAHB directly targets MCL-1, neutralizes its inhibitory interaction with pro-apoptotic BAK and sensitizes cancer cells to caspase-dependent apoptosis. By leveraging nature's solution to ligand selectivity, we generated an MCL-1-specific agent that defines the structural and functional features of targeted MCL-1 inhibition.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Apoptosis / drug effects*
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Caspase 3 / metabolism
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Caspase 7 / metabolism
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Cell Survival
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Cross-Linking Reagents
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Crystallography, X-Ray
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Cytochromes c / metabolism
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Enzyme Activation / drug effects
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Humans
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Immunoprecipitation
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Jurkat Cells
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Mitochondria / enzymology
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Mitochondria / metabolism
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Models, Molecular
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Molecular Sequence Data
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Myeloid Cell Leukemia Sequence 1 Protein
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Peptides / chemical synthesis
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Peptides / pharmacology
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Protein Binding
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Protein Structure, Secondary
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / chemistry*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-bcl-2 / pharmacology
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2 Homologous Antagonist-Killer Protein / physiology
Substances
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Cross-Linking Reagents
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Myeloid Cell Leukemia Sequence 1 Protein
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Peptides
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Proto-Oncogene Proteins c-bcl-2
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bcl-2 Homologous Antagonist-Killer Protein
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Cytochromes c
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Caspase 3
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Caspase 7