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

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• 作者：Lele Zhao ; Danyan Cao ; Tiantian Chen ; Yingqing Wang ; Zehong Miao ; Yechun Xu ; Wuyan Chen ; Xin Wang ; Yanlian Li ; Zhiyan Du ; Bing Xiong ; Jian Li ; Chunyan Xu ; Naixia Zhang ; Jianhua He ; Jingkang Shen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 23, 2013
• 年：2013
• 卷：56
• 期：10
• 页码：3833-3851
• 全文大小：927K
• 年卷期：v.56,no.10(May 23, 2013)
• ISSN：1520-4804

文摘

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.