2. Academic Validation
  3. Y08060: A Selective BET Inhibitor for Treatment of Prostate Cancer

Y08060: A Selective BET Inhibitor for Treatment of Prostate Cancer

  • ACS Med Chem Lett. 2018 Feb 13;9(3):262-267. doi: 10.1021/acsmedchemlett.8b00003.
Qiuping Xiang 1 2,  Yan Zhang 1 2,  Jiaguo Li 1 3,  Xiaoqian Xue 1 2,  Chao Wang 1,  Ming Song 1,  Cheng Zhang 1 3,  Rui Wang 1,  Chenchang Li 1 3,  Chun Wu 1,  Yulai Zhou 3,  Xiaohong Yang 3,  Guohui Li 4,  Ke Ding 5,  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 School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
  • 4 Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
  • 5 School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
PMID: 29541371 DOI: 10.1021/acsmedchemlett.8b00003
Abstract

Prostate Cancer is a commonly diagnosed Cancer and a leading cause of cancer-related deaths. The bromodomain and extra terminal domain (BET) family proteins have emerged as potential therapeutic targets for the treatment of castration-resistant prostate Cancer. A series of 2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives were designed and synthesized as selective bromodomain containing protein 4 (BRD4) inhibitors. The compounds potently inhibit BRD4(1) with nanomolar IC50 values and exhibit high selectivity over most non-BET subfamily members. One of the representative compounds 36 (Y08060) effectively suppresses cell growth, colony formation, and expression of Androgen Receptor (AR), AR regulated genes, and MYC in prostate Cancer cell lines. In in vivo studies, 36 demonstrates a good PK profile with high oral bioavailability (61.54%) and is a promising lead compound for further prostate Cancer drug development.

Figures