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

被引：4
|
作者：
Li, Junhua [1 ]
Zhu, Run [1 ,2 ]
Zhuang, Xiaoxi [1 ]
Zhang, Cheng [1 ]
Shen, Hui [1 ]
Wu, Xishan [1 ]
Zhang, Maofeng [3 ]
Huang, Cen [4 ]
Xiang, Qiuping [5 ]
Zhao, Linxiang [2 ]
Xu, Yong [1 ,6 ,7 ]
Zhang, Yan [1 ,6 ,7 ]
机构：
[1] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Ctr Chem Biol & Drug Discovery, 190 Kaiyuan Ave, Guangzhou 510530, Peoples R China
[2] Shenyang Pharmaceut Univ, Key Lab Struct Based Drugs Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China
[3] Suzhou Vocat Hlth Coll, 28 Kehua Rd, Suzhou 215009, Peoples R China
[4] Jiangsu S&T Exchange Ctr Foreign Countries, 175 Longpan Rd, Nanjing 210042, Peoples R China
[5] Univ Chinese Acad Sci, Ningbo Inst Life & Hlth Ind, Ningbo 315000, Peoples R China
[6] China New Zealand Joint Lab Biomed & Hlth, Guangzhou 510530, Peoples R China
[7] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, Guangzhou 510530, Peoples R China
来源：
BIOORGANIC CHEMISTRY | 2023年 / 135卷
基金：
国家重点研发计划; 中国国家自然科学基金;
关键词：
BET; Bromodomain; Bivalent Inhibitor; Cancer; BROMODOMAIN; PROTEINS;
D O I：
10.1016/j.bioorg.2023.106495
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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 tar-gets 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 mu M. 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.
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页数：15
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