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Zhao, Yujun; Zhou, Bing; Bai, Longchuan; Liu, Liu; Yang, Chao-Yie; Meagher, Jennifer L; Stuckey, Jeanne A; McEachern, Donna; Przybranowski, Sally; Wang, Mi; Ran, Xu; Aguilar, Angelo; Hu, Yang; Kampf, Jeff W; Li, Xiaoqin; Zhao, Ting; Li, Siwei; Wen, Bo; Sun, Duxin; Wang, Shaomeng
Journal of medicinal chemistry, 07/2018, Letnik: 61, Številka: 14Journal Article
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 NH-pyrazole group into the 9H-pyrimido4,5-bindole 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 in 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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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