TY - JOUR
T1 - A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival
AU - Cohen, Nicole A.
AU - Stewart, Michelle L.
AU - Gavathiotis, Evripidis
AU - Tepper, Jared L.
AU - Bruekner, Susanne R.
AU - Koss, Brian
AU - Opferman, Joseph T.
AU - Walensky, Loren D.
N1 - Funding Information:
We thank Eric D. Smith for editorial and graphics assistance, the Harvard Institute for Chemical and Cellular Biology for access to their chemical libraries and screening facility, Greg H. Bird for peptide synthesis, CreaGen Biosciences for MIM1 resynthesis and characterization, and the laboratory of Dr. Kalle Gehring for MCL-1 NMR assignments. This work was supported by an ARRA Supplement to National Institutes of Health (NIH) Grant P01CA92625 and a Stand Up to Cancer Innovative Research Grant to L.D.W. and NIH Grant RO1HL102175 and American Cancer Society award RSG-10-255-01-LIB to J.T.O. L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics.
PY - 2012/9/21
Y1 - 2012/9/21
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chembiol.2012.07.018
DO - 10.1016/j.chembiol.2012.07.018
M3 - Article
C2 - 22999885
AN - SCOPUS:84866654914
SN - 1074-5521
VL - 19
SP - 1175
EP - 1186
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 9
ER -
