Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening

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• 作者：Fanwang Meng ; Sufang Cheng ; Hong Ding ; Shien Liu ; Yan Liu ; Kongkai Zhu ; Shijie Chen ; Junyan Lu ; Yiqian Xie ; Linjuan Li ; Rongfeng Liu ; Zhe Shi ; Yu Zhou ; Yu-Chih Liu ; Mingyue Zheng ; Hualiang Jiang ; Wencong Lu ; Hong Liu ; Cheng Luo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 22, 2015
• 年：2015
• 卷：58
• 期：20
• 页码：8166-8181
• 全文大小：769K
• ISSN：1520-4804

文摘

Histone methyltransferases are involved in various biological functions, and these methylation regulating enzymes鈥?abnormal expression or activity has been noted in several human cancers. Within this context, SET domain-containing (lysine methyltransferase) 7 (SET7, also called KMT7, SETD7, SET9) is of increasing significance due to its diverse roles in biological functions and diseases, such as diabetes, cancers, alopecia areata, atherosclerotic vascular disease, HIV, and HCV. In this study, DC-S100, which was discovered by pharmacophore- and docking-based virtual screening, was identified as the hit compound of SET7 inhibitor. Structure鈥揳ctivity relationship (SAR) analysis was performed on analogs of DC-S100 and according to the putative binding mode of DC-S100, structure modifications were made to improve its activity. Of note, compounds DC-S238 and DC-S239, with IC₅₀ values of 4.88 and 4.59 渭M, respectively, displayed selectivity for DNMT1, DOT1L, EZH2, NSD1, SETD8, and G9a. Taken together, DC-S238 and DC-S239 can serve as leads for further investigation as SET7 inhibitors and the chemical toolkits for functional biology studies of SET7.