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 2,3; Cheng, Sufang 4; Ding, Hong3 ; Liu, Shien 3; Liu, Yan 3; Zhu, Kongkai 3; Chen, Shijie 3; Lu, Junyan 3; Xie, Yiqian 3; Li, Linjuan 1,3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2015-10-22
卷号	58 期号:20 页码:8166-8181
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.5b01154
文献子类	Article
英文摘要	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.
资助项目	Hi-Tech Research and Development Program of China[2012AA020302] ; Hi-Tech Research and Development Program of China[2012AA01A305] ; Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[8143000629] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09507002] ; China Postdoctoral Science Foundation[2014M551474]
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
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000363915600019
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276355]
专题	药物化学研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物发现与设计中心药理学第一研究室战略规划处
通讯作者	Lu, Wencong
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China; 2.Shanghai Univ, Coll Sci, Dept Chem, Shanghai 200444, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, 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.