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Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain

文献类型：期刊论文

作者Zhao, Lele2; Cao, Danyan2; Chen, Tiantian2; Wang, Yingqing3; Miao, Zehong3; Xu, Yechun2; Chen, Wuyan2; Wang, Xin2; Li, Yardian2; Du, Zhiyan2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2013-05-23
卷号56期号:10页码:3833-3851
ISSN号0022-2623
DOI10.1021/jm301793a
文献子类Article
英文摘要Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also, the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype and other fragment hits described herein can stimulate researchers to develop more diversified bromodomain inhibitors.
WOS关键词SMALL-MOLECULE INHIBITORS ; NMR-SPECTROSCOPY ; LEAD DISCOVERY ; IN-VIVO ; CHROMATIN ; FAMILY ; PERMEABILITY ; OPTIMIZATION ; DOCKING ; BINDING
资助项目Program of Excellent Young Scientist of Chinese Academy of Sciences[KSCX2-EW-Q3-01] ; "Interdisciplinary Cooperation Team" Program for Science and Technology Innovation of the Chinese Academy of Sciences[00000000] ; "100 Talents Project" of CAS[00000000] ; The National Natural Science Foundation of China[81072580] ; The National Natural Science Foundation of China[91013010] ; The National Natural Science Foundation of China[21172233] ; National Program on Key Basic Research Project (973 Program)[2009CB940903]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000319650100006
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/277612]  
专题药物化学研究室
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
通讯作者Xiong, Bing
作者单位1.Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai 201204, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Zhao, Lele,Cao, Danyan,Chen, Tiantian,et al. Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain[J]. JOURNAL OF MEDICINAL CHEMISTRY,2013,56(10):3833-3851.
APA Zhao, Lele.,Cao, Danyan.,Chen, Tiantian.,Wang, Yingqing.,Miao, Zehong.,...&Shen, Jingkang.(2013).Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain.JOURNAL OF MEDICINAL CHEMISTRY,56(10),3833-3851.
MLA Zhao, Lele,et al."Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain".JOURNAL OF MEDICINAL CHEMISTRY 56.10(2013):3833-3851.

入库方式： OAI收割

来源：上海药物研究所

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