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

Nat Chem Biol. 2010 Aug;6(8):595-601. doi: 10.1038/nchembio.391. Epub 2010 Jun 20.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Apoptosis / drug effects*
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Survival
  • Cross-Linking Reagents
  • Crystallography, X-Ray
  • Cytochromes c / metabolism
  • Enzyme Activation / drug effects
  • Humans
  • Immunoprecipitation
  • Jurkat Cells
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptides / chemical synthesis
  • Peptides / pharmacology
  • Protein Binding
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / chemistry*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / pharmacology
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein / physiology


  • Cross-Linking Reagents
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptides
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • Cytochromes c
  • Caspase 3
  • Caspase 7