Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORγ inverse agonists against prostate cancer
Xi-shan Wu1,2,
Xiao-yu Luo1,2,3,
Cheng-chang Li1,2,
Xiao-fan Zhao4,
Cheng Zhang1,2,
Xiao-shan Chen1,2,3,
Zhi-fang Lu1,2,5,
Tong Wu1,2,5,
Hao-nan Yu1,2,
Chao Peng6,
Qing-qing Hu1,2,
Hui Shen1,2,
Yong Xu1,2,5,
Yan Zhang1,2
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
2 Guangzhou Medical University, Guangzhou 511436, China
3 University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China
4 GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China
5 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
6 Jiangsu S&T Exchange Center with Foreign Countries, No. 175 Longpan Road, Nanjing 210042, China
Correspondence to: Xi-shan Wu: wu_xishan@gibh.ac.cn, Yong Xu: xu_yong@gibh.ac.cn, Yan Zhang: zhang_yan2012@gibh.ac.cn,
DOI: 10.1038/s41401-024-01274-z
Received: 18 January 2024
Accepted: 24 March 2024
Advance online: 2 May 2024
Abstract
The retinoic acid receptor-related orphan receptor γ (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 RORγ inverse 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 RORγ transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγ LBD 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.
