title: The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Stewart
authors.forename: Emiko
authors.initials: E
authors.lastname: Fire
authors.forename: Amy E
authors.initials: AE
authors.lastname: Keating
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002470:Cell Survival; D003432:Cross-Linking Reagents; D018360:Crystallography, X-Ray; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D019169:Jurkat Cells; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism / Q000502:physiology
chemical_list: D003432:Cross-Linking Reagents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D045304:Cytochromes c; D053148:Caspase 3; D053179:Caspase 7