A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival

Nicole A. Cohen, Michelle L. Stewart, Evripidis Gavathiotis, Jared L. Tepper, Susanne R. Bruekner, Brian Koss, Joseph T. Opferman, Loren D. Walensky

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

Cancer cells hijack BCL-2 family survival proteins to suppress the death effectors and thereby enforce an immortal state. This is accomplished biochemically by an antiapoptotic surface groove that neutralizes the proapoptotic BH3 α helix of death proteins. Antiapoptotic MCL-1 in particular has emerged as a ubiquitous resistance factor in cancer. Although targeting the BCL-2 antiapoptotic subclass effectively restores the death pathway in BCL-2-dependent cancer, the development of molecules tailored to the binding specificity of MCL-1 has lagged. We previously discovered that a hydrocarbon-stapled MCL-1 BH3 helix is an exquisitely selective MCL-1 antagonist. By deploying this unique reagent in a competitive screen, we identified an MCL-1 inhibitor molecule that selectively targets the BH3-binding groove of MCL-1, neutralizes its biochemical lock-hold on apoptosis, and induces caspase activation and leukemia cell death in the specific context of MCL-1 dependence.

Original languageEnglish (US)
Pages (from-to)1175-1186
Number of pages12
JournalChemistry and Biology
Volume19
Issue number9
DOIs
StatePublished - Sep 21 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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