A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model  

作　　者：Xin-yue Wang Xin Chai Lu-hu Shan Xiao-hong Xu Lei Xu Ting-jun Hou Hui-yong Sun Dan Li 

机构地区：[1]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]Institute of Bioinformatics and Medical Engineering,School of Electrical and Information Engineering,Jiangsu University of Technology,Changzhou,213001,China [4]State Key Lab of CAD&CG,Zhejiang University,Hangzhou,310058,China [5]Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing,210009,China [6]Jinhua Institute of Zhejiang University,Jinhua,321000,China

出　　处：《Acta Pharmacologica Sinica》2024年第9期1978-1991,共14页中国药理学报（英文版）

基　　金：Zhejiang Provincial Natural Science Foundation of China(LD22H300001,2023C03110);National Natural Science Foundation of China(U21A20301).

摘　　要：Prostate cancer(PCa)is the second most prevalent malignancy among men worldwide.The aberrant activation of androgen receptor(AR)signaling has been recognized as a crucial oncogenic driver for PCa and AR antagonists are widely used in PCa therapy.To develop novel AR antagonist,a machine-learning MIEC-SVM model was established for the virtual screening and 51 candidates were selected and submitted for bioactivity evaluation.To our surprise,a new-scaffold AR antagonist C2 with comparable bioactivity with Enz was identified at the initial round of screening.C2 showed pronounced inhibition on the transcriptional function(IC_(50)=0.63μM)and nuclear translocation of AR and significant antiproliferative and antimetastatic activity on PCa cell line of LNCaP.In addition,C2 exhibited a stronger ability to block the cell cycle of LNCaP than Enz at lower dose and superior AR specificity.Our study highlights the success of MIEC-SVM in discovering AR antagonists,and compound C2 presents a promising new scaffold for the development of AR-targeted therapeutics.

关 键 词：prostate cancer androgen receptor antagonist virtual screening MIEC-SVM model machine learning 

分 类 号：R737.25[医药卫生—肿瘤]