2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of 1-(Indolizin-3-yl)ethan-1-ones as CBP Bromodomain Inhibitors for the Treatment of Prostate Cancer

Design, Synthesis, and Biological Evaluation of 1-(Indolizin-3-yl)ethan-1-ones as CBP Bromodomain Inhibitors for the Treatment of Prostate Cancer

  • J Med Chem. 2022 Jan 13;65(1):785-810. doi: 10.1021/acs.jmedchem.1c01864.
Qiuping Xiang 1,  Chao Wang 1 2,  Tianbang Wu 1,  Cheng Zhang 1,  Qingqing Hu 1 2,  Guolong Luo 1 2,  Jiankang Hu 1 2,  Xiaoxi Zhuang 1,  Lingjiao Zou 1,  Hui Shen 1 2,  Xishan Wu 1,  Yan Zhang 1,  Xiangqian Kong 3,  Jinsong Liu 3,  Yong Xu 1 4 3
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Guangzhou Medical University, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 2 University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 4 China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou 510530, China.
PMID: 34962793 DOI: 10.1021/acs.jmedchem.1c01864
Abstract

CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) is a potential target for prostate Cancer treatment. Herein, we report the structural optimization of a series of 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led to compound 9g (Y08284), which possesses good liver microsomal stability and pharmacokinetic properties (F = 25.9%). Furthermore, the compound is able to inhibit CBP bromodomain as well as the proliferation, colony formation, and migration of prostate Cancer cells. Additionally, the new inhibitor shows promising antitumor efficacy in a 22Rv1 xenograft model (TGI = 88%). This study provides new lead compounds for further development of drugs for the treatment of prostate Cancer.

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