Journal
FEBS LETTERS
Volume 591, Issue 1, Pages 240-251Publisher
WILEY-BLACKWELL
DOI: 10.1002/1873-3468.12497
Keywords
apoptosis; cancer; drug discovery; myeloid cell leukemia 1; structure-based drug design
Funding
- U.S. National Institutes of Health, NIH Director's Pioneer Award [DP1OD006933/DP1CA174419]
- NCI Experimental Therapeutics (NExT) Program under the Leidos Biomed Prime [BOA29XS129TO22, HHSN261200800001E]
- NCI SPORE grant in breast cancer [P50CA098131]
- NIH SIG Grant [1S-10RR025677-01]
- Vanderbilt University matching funds
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DEAC02-06CH11357]
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Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors.
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