2. Academic Validation
  3. Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC)

Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC)

  • J Med Chem. 2018 Apr 12;61(7):3037-3058. doi: 10.1021/acs.jmedchem.8b00103.
Maofeng Zhang 1 2,  Yan Zhang 1 2,  Ming Song 1,  Xiaoqian Xue 1 2,  Junjian Wang 3,  Chao Wang 1,  Cheng Zhang 1 4,  Chenchang Li 1 4,  Qiuping Xiang 1 2,  Lingjiao Zou 1 2,  Xishan Wu 1 2,  Chun Wu 1,  Baijun Dong 5,  Wei Xue 5,  Yulai Zhou 4,  Hongwu Chen 3,  Donghai Wu 1,  Ke Ding 6,  Yong Xu 1
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences ; Guangzhou Medical University , Guangzhou , China.
  • 2 University of Chinese Academy of Sciences , No. 19 Yuquan Road , Beijing 100049 , China.
  • 3 Department of Biochemistry and Molecular Medicine, School of Medicine , University of California, Davis , Sacramento , California 95817 , United States.
  • 4 School of Pharmaceutical Sciences , Jilin University , No. 1266 Fujin Road , Chaoyang District, Changchun , Jilin 130021 , China.
  • 5 Department of Urology, Renji Hospital, School of Medicine , Shanghai Jiao Tong University , Shanghai 200127 , China.
  • 6 School of Pharmacy , Jinan University , 601 Huangpu Avenue West , Guangzhou 510632 , China.
PMID: 29566488 DOI: 10.1021/acs.jmedchem.8b00103
Abstract

The bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate Cancer (CRPC). Here, we describe the design, optimization, and evaluation of benzo[ d]isoxazole-containing compounds as potent BET bromodomain inhibitors. Cocrystal structures of the representative inhibitors in complex with BRD4(1) provided solid structural basis for compound optimization. The two most potent compounds, 6i (Y06036) and 7m (Y06137), bound to the BRD4(1) bromodomain with Kd values of 82 and 81 nM, respectively. They also exhibited high selectivity over other non-BET subfamily members. The compounds potently inhibited cell growth, colony formation, and the expression of AR, AR regulated genes, and MYC in prostate Cancer cell lines. Compounds 6i and 7m also demonstrated therapeutic effects in a C4-2B CRPC xenograft tumor model in mice. These potent and selective BET inhibitors represent a new class of compounds for the development of potential therapeutics against CRPC.

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