Lead discovery, chemical optimization, and biological evaluation studies of novel histone methyltransferase SET7 small-molecule inhibitors

doi:10.1016/j.bmcl.2020.127061

	Lead discovery, chemical optimization, and biological evaluation studies of novel histone methyltransferase SET7 small-molecule inhibitors
	Hou, Zeng 2,3; Min, Wenjian 1,4,5; Zhang, Rukang 6,7; Niu, Ao 1,4; Li, Yuanqing 2,3; Cao, Liyuan 2; Han, Jie 2,3; Luo, Cheng 2,3; Yang, Peng 1,4,5; Ding, Hong 1,2,4
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2020-05-01
卷号	30 期号:9 页码:10
关键词	Histone methylation SET7 Small-molecule inhibitor Virtual screening Molecular probe
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2020.127061
通讯作者	Yang, Peng(pengyang@cpu.edu.cn) ; Ding, Hong(hding@simm.ac.cn)
英文摘要	The post-translational modifications of histones, including histone methylation and demethylation, control the expression switch of multiple genes. SET domain-containing lysine methyltransferase 7 (SET7) is the only methyltransferase, which can specifically monomethylate lysine-4 of histone H3 (H3K4mel) and play critical roles in various diseases, including breast cancer, hepatitis C virus (HCV), atherosclerotic vascular disease, diabetes, prostate cancer, hepatocellular carcinoma, and obesity. However, several known SET7 inhibitors exhibit weak activity or poor selectivity. Therefore, the development of novel SET7 inhibitors is highly desirable and of great clinical value. In this study, we identified 2-79 as a new hit compound by structure-based virtual screening and further AlphaLISA-based biochemical evaluation. Via chemical optimization, the synthesized compound DC21 was confirmed as a potent SET7 inhibitor with an IC50, value of 15.93 mu M. The interaction between DC21 and SET7 was also validated through SPR experiment. Especially, DC21 retarded proliferation of MCF7 cells with an IC50, value of 25.84 mu M in cellular level. In addition, DC21 has good selectivity for several other epigenetic targets, such as SUV39H1, G9a, NSD1, DOT1L and MOF. DC21 can serve as a lead compound to develop more potential SET7 inhibitors and as a chemical probe for SET7 biological function studies.
资助项目	Ministry of Science and Technology of China (National Key R&D Program of China)[2017YFB0202600] ; Personalized Medicines Molecular Signature-based Drug Discovery and Development (Strategic Priority Research Program of the Chinese Academy of Sciences)[XDA12020368] ; Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University[SKLNMZZRC07] ; Double First-Class University Project[CPU2018GF04]
WOS关键词	TRANSCRIPTION ; METHYLATION ; PROTEIN ; FAMILY
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000522861200014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280818]
专题	中国科学院上海药物研究所
通讯作者	Yang, Peng; Ding, Hong
作者单位	1.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 4.China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimisat, Nanjing 210009, Peoples R China 5.China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 211198, Peoples R China 6.Emory Univ, Dept Hematol & Med Oncol, Sch Med, Atlanta, GA 30322 USA 7.Emory Univ, Winship Canc Inst, Sch Med, Atlanta, GA 30322 USA
推荐引用方式 GB/T 7714	Hou, Zeng,Min, Wenjian,Zhang, Rukang,et al. Lead discovery, chemical optimization, and biological evaluation studies of novel histone methyltransferase SET7 small-molecule inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2020,30(9):10.
APA	Hou, Zeng.,Min, Wenjian.,Zhang, Rukang.,Niu, Ao.,Li, Yuanqing.,...&Ding, Hong.(2020).Lead discovery, chemical optimization, and biological evaluation studies of novel histone methyltransferase SET7 small-molecule inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,30(9),10.
MLA	Hou, Zeng,et al."Lead discovery, chemical optimization, and biological evaluation studies of novel histone methyltransferase SET7 small-molecule inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 30.9(2020):10.