Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain.
Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain.
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DOI：
10.1021/jm301793a
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发表时间：
2013-05
影响因子：
7.3
通讯作者：
Lele Zhao;D. Cao;Tiantian Chen;Ying-Qing Wang;Z. Miao;Yechun Xu;Wu-yan Chen;Xin Wang;Yanlian Li
中科院分区：
文献类型：
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作者：
Lele Zhao;D. Cao;Tiantian Chen;Ying-Qing Wang;Z. Miao;Yechun Xu;Wu-yan Chen;Xin Wang;Yanlian Li
组蛋白乙酰赖氨酸的识别是表观遗传调控的重要过程，它是由一个称为溴结构域的蛋白质模块介导的。为了有助于开发成布罗莫结构域抑制剂的新型支架，我们利用基于片段的药物发现方法。通过连续应用对接和X射线晶体学，我们能够从60多个晶体的衍射中鉴定出9个碎片。在目前的工作中，我们描述了其中的四个，并进行了综合铅优化片段8，它带有一个2-噻唑烷酮的核心。经过几轮结构导向修饰后，我们通过调节体外药代动力学研究和细胞活性测定来评估2-噻唑烷酮的可药性。结果表明，两种有效的2-噻唑烷酮类化合物具有良好的代谢稳定性。此外，细胞测定证实了2-噻唑烷酮的活性。总之，我们希望本文所述的鉴定的2-噻唑烷酮化学型和其他片段命中物可以刺激研究人员开发更多样化的布罗莫结构域抑制剂。
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.