1区 · 医学
Article
作者: Li, Siwei ; Zhao, Yujun ; Sun, Duxin ; Bai, Longchuan ; Yang, Chao-Yie ; Kampf, Jeff W. ; Liu, Liu ; Zhao, Ting ; Aguilar, Angelo ; McEachern, Donna ; Wang, Mi ; Meagher, Jennifer L. ; Wen, Bo ; Przybranowski, Sally ; Wang, Shaomeng ; Hu, Yang ; Stuckey, Jeanne A. ; Zhou, Bing ; Li, Xiaoqin ; Ran, Xu
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-pyrimido[4,5- b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with Ki 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.