期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 14, 页码 6110-6120出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00483
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资金
- Prostate Cancer Foundation
- OncoFusion Therapeutics, Inc.
- University of Michigan Prostate Cancer SPORE grant (NIH/NCI) [P50 CA186786]
- University of Michigan Comprehensive Cancer Core grant (NIH/NCI) [P30CA046592]
- U.S. DOE [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- NATIONAL CANCER INSTITUTE [P30CA046592, P50CA186786] Funding Source: NIH RePORTER
We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NHpyrazole group into the 9H-pyrimido[4,5-b] indole core, we identified a series of compounds that bind to BRD4 BD1 protein with K-i values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in0 both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development.
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