Rational design, synthesis and biological evaluation of benzo[d]isoxazole derivatives as potent BET bivalent inhibitors for potential treatment of prostate cancer

Junhua Li; Run Zhu; Xiaoxi Zhuang; Cheng Zhang; Hui Shen; Xishan Wu; Maofeng Zhang; Cen Huang; Qiuping Xiang; Linxiang Zhao; Yong Xu; Yan Zhang

doi:10.1016/j.bioorg.2023.106495

Rational design, synthesis and biological evaluation of benzo[d]isoxazole derivatives as potent BET bivalent inhibitors for potential treatment of prostate cancer

Bioorg Chem. 2023 Jun:135:106495. doi: 10.1016/j.bioorg.2023.106495. Epub 2023 Mar 28.

Authors

Junhua Li¹, Run Zhu², Xiaoxi Zhuang¹, Cheng Zhang¹, Hui Shen¹, Xishan Wu¹, Maofeng Zhang³, Cen Huang⁴, Qiuping Xiang⁵, Linxiang Zhao⁶, Yong Xu⁷, Yan Zhang⁸

Affiliations

¹ Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
² Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ Suzhou Vocational Health College, No. 28 Kehua Road, Suzhou 215009, China.
⁴ Jiangsu S&T Exchange Center with Foreign Countries, No. 175 Longpan Road, Nanjing 210042, China.
⁵ Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo 315000, China.
⁶ Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
⁷ Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou 510530, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. Electronic address: xu_yong@gibh.ac.cn.
⁸ Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou 510530, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. Electronic address: zhang_yan2012@gibh.ac.cn.

PMID: 37004437
DOI: 10.1016/j.bioorg.2023.106495

Abstract

Multivalency is an attractive strategy for effective binding to target protein. Bromodomain and extra-terminal (BET) family features two tandem bromodomains (BD1, BD2), which are considered to be potential new targets for prostate cancer. Herein, we report the rational design, optimization, and evaluation of a class of novel BET bivalent inhibitors based on our monovalent BET inhibitor 7 (Y06037). The representative bivalent inhibitor 17b effectively inhibited the cell growth of LNCaP, exhibiting 32 folds more potency than monovalent inhibitor 7. Besides, 17b induced 95.1 % PSA regression in LNCaP cell at 2 μM. Docking study was further carried out to reveal the potential binding mode of 17b with two BET bromodomains. Our study demonstrates that 17b (Y13021) is a promising BET bivalent inhibitor for the treatment of prostate cancer.

Keywords: BET; Bivalent Inhibitor; Bromodomain; Cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation
Humans
Isoxazoles / pharmacology
Male
Prostatic Neoplasms* / drug therapy
Protein Domains
Transcription Factors* / metabolism

Substances

Transcription Factors
Isoxazoles