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

doi:10.1021/acs.jmedchem.5b01154

	Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening
	Meng, Fanwang 1,2; Cheng, Sufang 3; Ding, Hong 2; Liu, Shien 2; Liu, Yan 2; Zhu, Kongkai 2; Chen, Shijie 2; Lu, Junyan 2; Xie, Yiqian 2; Li, Linjuan2,4 ; Liu, Rongfeng 5; Shi, Zhe 5; Zhou, Yu 3; Liu, Yu-Chih 5; Zheng, Mingyue 2; Jiang, Hualiang2,4 ; Lu, Wencong 1; Liu, Hong3 ; Luo, Cheng 2
	2015-10-22
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
卷号	58 期号:20 页码:8166-8181
发表状态	已发表
DOI	10.1021/acs.jmedchem.5b01154
摘要	Histone methyltransferases are involved in various biological functions, and these methylation regulating enzymes' 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-activity 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 mu 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.
收录类别	SCI ; IC
语种	英语
资助项目	China Postdoctoral Science Foundation[2014M551474]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000363915600019
出版者	AMER CHEMICAL SOC
WOS关键词	SMALL-MOLECULE INHIBITORS ; LYSINE METHYLTRANSFERASE ; DRUG DISCOVERY ; IN-VIVO ; ARGININE METHYLTRANSFERASES ; CELLULAR-ACTIVITY ; HISTONE/PROTEIN METHYLTRANSFERASE ; PROTEIN METHYLTRANSFERASES ; TRANSCRIPTIONAL ACTIVITY ; BIOLOGICAL EVALUATION
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2107
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_柳红组免疫化学研究所_特聘教授组_蒋华良组生命科学与技术学院_博士生
通讯作者	Lu, Wencong
作者单位	1.Shanghai Univ, Coll Sci, Dept Chem, Shanghai 200444, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China 5.Shanghai ChemPartner Co Ltd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Meng, Fanwang,Cheng, Sufang,Ding, Hong,et al. Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening[J]. JOURNAL OF MEDICINAL CHEMISTRY,2015,58(20):8166-8181.
APA	Meng, Fanwang.,Cheng, Sufang.,Ding, Hong.,Liu, Shien.,Liu, Yan.,...&Luo, Cheng.(2015).Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening.JOURNAL OF MEDICINAL CHEMISTRY,58(20),8166-8181.
MLA	Meng, Fanwang,et al."Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening".JOURNAL OF MEDICINAL CHEMISTRY 58.20(2015):8166-8181.