The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer.

Publication Type:

Journal Article


Nat Chem Biol, Volume 6, Issue 8, p.595-601 (2010)


Amino Acid Sequence, Apoptosis, bcl-2 Homologous Antagonist-Killer Protein, Caspase 3, Caspase 7, Cell Survival, Cross-Linking Reagents, Crystallography, X-Ray, Cytochromes c, Enzyme Activation, Humans, Immunoprecipitation, Jurkat Cells, Mitochondria, Models, Molecular, Molecular Sequence Data, Myeloid Cell Leukemia Sequence 1 Protein, Peptides, Protein Binding, Protein Structure, Secondary, Proto-Oncogene Proteins c-bcl-2


<p>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.</p>