Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
J Med Chem. 2013 May 23;56(10):3833-51. doi: 10.1021/jm301793a. Epub 2013 May 14.
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.
识别组蛋白乙酰赖氨酸是一种重要的表观遗传调控过程，由一个称为溴结构域的蛋白质模块介导。为了为开发溴结构域抑制剂提供新的支架，我们采用了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，我们从超过 60 个晶体中鉴定出 9 个片段命中。在本工作中，我们描述了其中的四个，并对带有 2-噻唑烷酮核心的片段 8 进行了综合的先导优化。经过几轮基于结构的修饰，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-噻唑烷酮的成药性。结果表明，两种具有良好代谢稳定性的 2-噻唑烷酮类化合物。此外，细胞测定也证实了 2-噻唑烷酮类化合物的活性。总之，我们希望所鉴定的 2-噻唑烷酮类化学型和本文描述的其他片段命中能够激发研究人员开发更多多样化的溴结构域抑制剂。
