Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance  

作　　者：Xin Chai Xue-ping Hu Xin-yue Wang Hua-ting Wang Jin-ping Pang Wen-fang Zhou Jia-ning Liao Lu-hu Shan Xiao-hong Xu Lei Xu Hong-guang Xia Ting-jun Hou Dan Li 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2023年第7期1500-1518,共19页中国药理学报（英文版）

基　　金：National Key R&D Program of China(2019YFE0111300);National Natural Science Foundation of China(22220102001,22273049);Zhejiang Provincial Natural Science Foundation of China(LD22H300001).

摘　　要：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(IC_(50)=0.394μM)and GR(IC_(50)=17.81μM).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.

关 键 词：prostate cancer androgen receptor glucocorticoid receptor dual antagonists antiandrogen resistance 

分 类 号：R965[医药卫生—药理学]