A Competitive Stapled Peptide Screen Identifies a Selective Small Molecule that Overcomes MCL-1-Dependent Leukemia Cell Survival.
Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Bruekner SR, Koss B, Opferman JT, Walensky LD., Chem Biol. 2012, 19, 1175-86. doi: 10.1016/j.chembiol.2012.07.018.
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 Î± 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.
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