Discovery of novel antagonists targeting the DNA binding domain of androgen receptor by integrated docking-based virtual screening and bioassays  

作　　者：Jin-ping Pang Chao Shen Wen-fang Zhou Yun-xia Wang Lu-hu Shan Xin Chai Ying Shao Xue-ping Hu Feng Zhu Dan-yan Zhu Li Xiao Lei Xu Xiao-hong Xu Dan Li Ting-jun Hou 

机构地区：[1]Hangzhou Institute of Innovative Medicine,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,310058,China [2]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,China [3]School of Life Science,Huzhou University,Huzhou,313000,China [4]Institute of Bioinformatics and Medical Engineering,School of Electrical and Information Engineering,Jiangsu University of Technology,Changzhou,213001,China [5]State Key Lab of CAD&CG,Zhejiang University,Hangzhou,310058,China

出　　处：《Acta Pharmacologica Sinica》2022年第1期229-239,共11页中国药理学报（英文版）

基　　金：This study was supported by the Key R&D Program of Zhejiang Province(2020C03010),National Natural Science Foundation of China(81773632),Zhejiang Provincial Natural Science Foundation of China(LZ19H300001),and the Key R&D Program of Zhejiang Province(2019C02024).

摘　　要：Androgen receptor(AR),a ligand-activated transcription factor,is a master regulator in the development and progress of prostate cancer(PCa).A major challenge for the clinically used AR antagonists is the rapid emergence of resistance induced by the mutations at AR ligand binding domain(LBD),and therefore the discovery of novel anti-AR therapeutics that can combat mutation-induced resistance is quite demanding.Therein,blocking the interaction between AR and DNA represents an innovative strategy.However,the hits confirmed targeting on it so far are all structurally based on a sole chemical scaffold.In this study,an integrated docking-based virtual screening(VS)strategy based on the crystal structure of the DNA binding domain(DBD)of AR was conducted to search for novel AR antagonists with new scaffolds and 2-(2-butyl-1,3-dioxoisoindoline-5-carboxamido)−4,5-dimethoxybenzoicacid(Cpd39)was identified as a potential hit,which was competent to block the binding of AR DBD to DNA and showed decent potency against AR transcriptional activity.Furthermore,Cpd39 was safe and capable of effectively inhibiting the proliferation of PCa cell lines(i.e.,LNCaP,PC3,DU145,and 22RV1)and reducing the expression of the genes regulated by not only the full-length AR but also the splice variant AR-V7.The novel AR DBD-ARE blocker Cpd39 could serve as a starting point for the development of new therapeutics for castration-resistant PCa.

关 键 词：androgen receptor DNA binding domain ANTAGONIST prostate cancer virtual screening molecular docking 

分 类 号：R96[医药卫生—药理学]