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

92 Citations (Scopus)

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

Fingerprint

Cell Survival
Leukemia
Cells
Peptides
Molecules
R Factors
Cell death
Caspases
Hydrocarbons
Neoplasms
Proteins
Chemical activation
Apoptosis
Cell Death

ASJC Scopus subject areas

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

Cite this

A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. / Cohen, Nicole A.; Stewart, Michelle L.; Gavathiotis, Evripidis; Tepper, Jared L.; Bruekner, Susanne R.; Koss, Brian; Opferman, Joseph T.; Walensky, Loren D.

In: Chemistry and Biology, Vol. 19, No. 9, 21.09.2012, p. 1175-1186.

Research output: Contribution to journalArticle

Cohen, Nicole A. ; Stewart, Michelle L. ; Gavathiotis, Evripidis ; Tepper, Jared L. ; Bruekner, Susanne R. ; Koss, Brian ; Opferman, Joseph T. ; Walensky, Loren D. / A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. In: Chemistry and Biology. 2012 ; Vol. 19, No. 9. pp. 1175-1186.
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