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Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain
Zhao, Lele; Cao, Danyan; Chen, Tiantian; Wang, Yingqing; Miao, Zehong; Xu, Yechun; Chen, Wuyan; Wang, Xin; Li, Yardian; Du, Zhiyan; Xiong, Bing; Li, Jian; Xu, Chunyan(徐春艳); Zhang, Naixia; He, Jianhua(何建华); Shen, Jingkang
2013
Source PublicationJOURNAL OF MEDICINAL CHEMISTRY
ISSN0022-2623
Volume56Issue:10Pages:CONCATENATE(Sheet1!I134,-Sheet1!J134)
AbstractRecognizing 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.
Indexed BySCI
Language英语
Funding Project应物所项目组
WOS IDWOS:000319650100006
Citation statistics
Cited Times:89[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.sinap.ac.cn/handle/331007/13757
Collection中科院上海应用物理研究所2011-2020年
Recommended Citation
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):CONCATENATE(Sheet1!I134,-Sheet1!J134).
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),CONCATENATE(Sheet1!I134,-Sheet1!J134).
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):CONCATENATE(Sheet1!I134,-Sheet1!J134).
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