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Fragment-Based Drug Discovery of 2-Thiazolidinones as BRD4 Inhibitors: 2. Structure-Based Optimization

文献类型：期刊论文

作者Zhao, Lele1; Wang, Yingqing2; Cao, Danyan; Chen, Tiantian3; Wang, Qi1; Li, Yanlian1; Xu, Yechun3; Zhang, Naixia1; Wang, Xin1; Chen, Danqi1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2015-02-12
卷号58期号:3页码:1281-1297
ISSN号0022-2623
DOI10.1021/jm501504k
文献子类Article
英文摘要The signal transduction of acetylated histone can be processed through a recognition module, bromodomain. Several inhibitors targeting BRD4, one of the bromodomain members, are in clinical trials as anticancer drugs. Hereby, we report our efforts on discovery and optimization of a new series of 2-thiazolidinones as BRD4 inhibitors along our previous study. In this work, guided by crystal structure analysis, we reversed the sulfonamide group and identified a new binding mode. A structure-activity relationship study on this new series led to several potent BRD4 inhibitors with IC50 of about 0.05-0.1 mu M in FP binding assay and GI50 of 0.1-0.3 mu M in cell based assays. To complete the lead-like assessment of this series, we further checked its effects on BRD4 downstream protein c-Myc, investigated its selectivity among five different bromodomain proteins, as well as the metabolic stability test, and reinforced the utility of 2-thiazolidinone scaffold as BET bromodomain inhibitors in novel anticancer drug development.
WOS关键词LYSINE ACETYLATION ; BROMODOMAIN INHIBITORS ; BET BROMODOMAINS ; REGULATOR ; IDENTIFICATION ; CHROMATIN ; DISEASES ; LIGANDS ; FAMILY ; MODE
资助项目"Interdisciplinary Cooperation Team" Program for Science and Technology Innovation of the Chinese Academy of Sciences[00000000] ; "100 Talents Project" of CAS[00000000] ; National Natural Science Foundation of China[81072580] ; National Natural Science Foundation of China[81330076] ; National Natural Science Foundation of China[91013010] ; National Natural Science Foundation of China[81025020] ; National Natural Science Foundation of China[81321092] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2014ZX09507-002] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2013ZX09507001]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000349573800020
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/276642]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药物化学研究室
通讯作者Xiong, Bing
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China;
4.Shanghai Pharmaceut Holding Co, Cent Res Inst, Shanghai 201203, Peoples R China;
5.Shanghai ChemPartner Co Ltd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhao, Lele,Wang, Yingqing,Cao, Danyan,et al. Fragment-Based Drug Discovery of 2-Thiazolidinones as BRD4 Inhibitors: 2. Structure-Based Optimization[J]. JOURNAL OF MEDICINAL CHEMISTRY,2015,58(3):1281-1297.
APA Zhao, Lele.,Wang, Yingqing.,Cao, Danyan.,Chen, Tiantian.,Wang, Qi.,...&Xiong, Bing.(2015).Fragment-Based Drug Discovery of 2-Thiazolidinones as BRD4 Inhibitors: 2. Structure-Based Optimization.JOURNAL OF MEDICINAL CHEMISTRY,58(3),1281-1297.
MLA Zhao, Lele,et al."Fragment-Based Drug Discovery of 2-Thiazolidinones as BRD4 Inhibitors: 2. Structure-Based Optimization".JOURNAL OF MEDICINAL CHEMISTRY 58.3(2015):1281-1297.

入库方式： OAI收割

来源：上海药物研究所

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