Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance
Xin Chai1,2,
Xue-ping Hu3,
Xin-yue Wang1,
Hua-ting Wang1,
Jin-ping Pang1,
Wen-fang Zhou1,
Jia-ning Liao1,
Lu-hu Shan4,
Xiao-hong Xu4,
Lei Xu5,
Hong-guang Xia2,6,
Ting-jun Hou1,
Dan Li1,7
1 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
2 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, Zhejiang, China
3 Institute of Molecular Sciences and Engineering, Institute of Frontier and Interdisciplinary Science, Shandong University, Qingdao 266237, Shandong, China
4 Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang, China
5 Department of Biochemistry & Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
6 Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, Jiangsu, China
7 Jinhua Institute of Zhejiang University, Jinhua 321099, Zhejiang, China
Correspondence to: Hong-guang Xia: hongguangxia@zju.edu.cn, Ting-jun Hou: tingjunhou@zju.edu.cn, Dan Li: lidancps@zju.edu.cn,
DOI: 10.1038/s41401-022-01038-7
Received: 28 October 2022
Accepted: 1 December 2022
Advance online: 13 January 2023
Abstract
As a major class of medicine for treating the lethal type of castration-resistant prostate cancer (PCa), long-term use of androgen receptor (AR) antagonists commonly leads to antiandrogen resistance. When AR signaling pathway is blocked by AR-targeted therapy, glucocorticoid receptor (GR) could compensate for AR function especially at the late stage of PCa. AR-GR dual antagonist is expected to be a good solution for this situation. Nevertheless, no effective non-steroidal AR-GR dual antagonist has been reported so far. In this study, an AR-GR dual binder H18 was first discovered by combining structure-based virtual screening and biological evaluation. Then with the aid of computationally guided design, the AR-GR dual antagonist HD57 was finally identified with antagonistic activity towards both AR (IC50 = 0.394 μM) and GR (IC50 = 17.81 μM). Moreover, HD57 could effectively antagonize various clinically relevant AR mutants. Further molecular dynamics simulation provided more atomic insights into the mode of action of HD57. Our research presents an efficient and rational strategy for discovering novel AR-GR dual antagonists, and the new scaffold provides important clues for the development of novel therapeutics for castration-resistant PCa.
