典型文献
Discovery of novel antagonists targeting the DNA binding domain of androgen receptor by integrated docking-based virtual screening and bioassays
文献摘要：
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,DU 145,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.
文献关键词：
中图分类号：
作者姓名：
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
作者机构：
Hangzhou Institute of Innovative Medicine,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China;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;School of Life Science,Huzhou University,Huzhou 313000,China;Institute of Bioinformatics and Medical Engineering,School of Electrical and Information Engineering,Jiangsu University of Technology,Changzhou 213001,China;State Key Lab of CAD&CG,Zhejiang University,Hangzhou 310058,China
文献出处：
引用格式：
[1]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-.Discovery of novel antagonists targeting the DNA binding domain of androgen receptor by integrated docking-based virtual screening and bioassays)[J].中国药理学报（英文版）,2022(01):229-239
A类：
dioxoisoindoline,carboxamido,dimethoxybenzoicacid,Cpd39
B类：
Discovery,novel,antagonists,targeting,binding,domain,androgen,receptor,by,integrated,docking,virtual,screening,bioassays,Androgen,ligand,activated,master,regulator,development,progress,prostate,cancer,PCa,major,challenge,clinically,used,rapid,emergence,resistance,induced,mutations,LBD,therefore,discovery,anti,therapeutics,that,combat,quite,demanding,Therein,blocking,interaction,between,represents,innovative,strategy,However,hits,confirmed,far,are,structurally,sole,chemical,In,this,study,VS,crystal,structure,DBD,was,conducted,search,new,scaffolds,butyl,identified,potential,which,competent,showed,decent,potency,against,transcriptional,activity,Furthermore,safe,capable,effectively,inhibiting,proliferation,cell,lines,LNCaP,PC3,DU,22RV1,reducing,expression,genes,regulated,not,only,full,length,also,splice,variant,V7,ARE,blocker,could,serve,starting,point,castration,resistant
AB值：
0.561488
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机标中图分类号，由域田数据科技根据网络公开资料自动分析生成，仅供学习研究参考。
