Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORγ inverse agonists against prostate cancer  

作　　者：Xi-shan Wu Xiao-yu Luo Cheng-chang Li Xiao-fan Zhao Cheng Zhang Xiao-shan Chen Zhi-fang Lu Tong Wu Hao-nan Yu Chao Peng Qing-qing Hu Hui Shen Yong Xu Yan Zhang 

机构地区：[1]State Key Laboratory of Respiratory Disease,China-New Zealand Joint Laboratory of Biomedicine and Health,Guangdong Provincial Key Laboratory of Biocomputing,Center for Chemical Biology and Drug Discovery,Joint School of Life Sciences,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,No.190 Kaiyuan Avenue,Guangzhou,510530 China,Guangzhou Medical University,Guangzhou,511436,China [2]University of Chinese Academy of Sciences,No.19 Yuquan Road,Beijing,100049,China [3]GMU-GIBH Joint School of Life Sciences,Guangzhou Medical University,Guangzhou,511436,China [4]Key Laboratory of Structure-Based Drug Design and Discovery,Ministry of Education,Shenyang Pharmaceutical University,Shenyang,110016,China [5]Jiangsu S&T Exchange Center with Foreign Countries,No.175 Longpan Road,Nanjing,210042,China

出　　处：《Acta Pharmacologica Sinica》2024年第9期1964-1977,共14页中国药理学报（英文版）

基　　金：National Key R&D Program of China(grant 2019YFE0123700 and 2022YFE0210600);National Natural Science Foundation of China(grant 82173745);Chinese Academy of Sciences STS Program(grant KFJ-STS-QYZX-090);Guangdong Basic and Applied Basic Research Foundation(grant 2023A1515010418 and 2020A1515110793);Science and Technology Program of Guangzhou,China(grant 2024A04J4313 and 202201010138);China Postdoctoral Science Foundation,the Guangdong Provincial Grant for Belt and Road Joint Laboratory(grant 2022A0505090006);Guangdong Provincial Postdoctoral Special Funding.

摘　　要：The retinoic acid receptor-related orphan receptorγ(RORγ)is regarded as an attractive therapeutic target for the treatment of prostate cancer.Herein,we report the identification,optimization,and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORγinverse agonists,starting from high throughput screening using a thermal stability shift assay(TSA).The representative compounds 13e(designated as XY039)and 14a(designated as XY077)effectively inhibited the RORγtranscriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes.The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγLBD complex with 13e.Both 13e and 14a demonstrated reasonable antiproliferative activity,potently inhibited colony formation and the expression of AR,AR regulated genes,and other oncogene in AR positive prostate cancer cell lines.Moreover,13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice.This work provides new and valuable lead compounds for further development of drugs against prostate cancer.

关 键 词：RORγ inverse agonists 1 2 3 4-tetrahydroquinoline derivatives prostate cancer 

分 类 号：R737.25[医药卫生—肿瘤]