1. Academic Validation
  2. Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor

Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor

  • J Med Chem. 2018 Jul 26;61(14):6110-6120. doi: 10.1021/acs.jmedchem.8b00483.
Yujun Zhao Bing Zhou Longchuan Bai Liu Liu Chao-Yie Yang Jennifer L Meagher Jeanne A Stuckey Donna McEachern Sally Przybranowski Mi Wang Xu Ran Angelo Aguilar Yang Hu Jeff W Kampf Xiaoqin Li Ting Zhao Siwei Li Bo Wen Duxin Sun Shaomeng Wang
Abstract

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.

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