期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 9, 页码 3794-3805出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501984f
关键词
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资金
- U.S. National Institutes of Health, NIH Director's Pioneer Award [DP1OD006933/DP1CA174419]
- NCI Experimental Therapeutics (NExT) Program under Leidos Biomed Prime [BOA29XS129TO22, HHSN261200800001E]
- career development award from NCI SPORE grant in breast cancer [P50CA098131]
- American Cancer Society (Postdoctoral Fellowship) [PF1110501CDD]
- NIH SIG Grant [1S-10RR025677-01]
- Vanderbilt University matching funds
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Cancer Research UK [11566] Funding Source: researchfish
Myeloid cell leuketinia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.
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