Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines

doi:10.1016/j.ejmech.2016.06.028

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	Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines
	Kondengaden, Shukkoor M.1,2; Luo, Liu-fei 3; Huang, Kenneth 1,2; Zhu, Mengyuan 1,2; Zang, Lanlan 1,2,4; Bataba, Eudoxie 1,2; Wang, Runling 4; Luo, Cheng5 ; Wang, Binghe 1,2; Li, Keqin Kathy 1,2,3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2016-10-21
卷号	122 页码:382-393
关键词	Lysine methyltransferase G9a inhibitor Leukemia MALDI-TOF assay
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2016.06.028
文献子类	Article
英文摘要	Lysine methyltransferase G9a regulates the transcription of multiple genes by primarily catalyzing mono and di-methylation of histone H3 lysine 9, as well as several non-histone lysine sites. An attractive therapeutic target in treating leukemia, knockout studies of G9a in mice have found dramatically slowed proliferation and self-renewal of acute myeloid leukemia (AML) cells due to the attenuation of HoxA9-dependent transcription. In this study, a series of compounds were identified as potential inhibitors through structure-based virtual screening. Among these compounds, a new G9a inhibitor, DCG066, was confirmed by in vitro biochemical, and cell based enzyme assays. DCG066 has a novel molecular scaffold unlike other G9a inhibitors presently available. Similar to G9a's histone substrate, DCG066 can bind directly to G9a and inhibit methyltransferase activity in vitro. In addition to suppressing G9a methyltransferase activity and reducing histone H3 methylation levels, DCG066 displays low cytotoxicity in leukemia cell lines with high levels of G9a expression, including K562. This work presents DCG066 as an inhibitor of G9a with a novel structure, providing both a lead in G9a inhibitor design and a means for probing the functionality of G9a. (C) 2016 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81270622] ; China 973 Program[2013CB733700] ; China 973 Program[2011CB510102] ; Georgia Research Alliance funding[00000000]
WOS关键词	PLURIPOTENT STEM-CELLS ; HISTONE METHYLTRANSFERASE ; DNA METHYLATION ; CHEMICAL PROBE ; GLP ; H3 ; TRIMETHYLATION ; SUV39H1 ; ANALOGS ; GENES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000383003900032
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275850]
专题	药物发现与设计中心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
通讯作者	Li, Keqin Kathy; Wang, Peng George
作者单位	1.Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA; 2.Georgia State Univ, Ctr Diagnost & Therapeut, Atlanta, GA 30303 USA; 3.Shanghai Jiao Tong Univ, State Key Lab Med Genom, Shanghai, Peoples R China; 4.Tianjin Med Univ, Sch Pharm, Tianjin Key Lab Technol Enabling Dev Clin Therape, Tianjin 300070, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Kondengaden, Shukkoor M.,Luo, Liu-fei,Huang, Kenneth,et al. Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2016,122:382-393.
APA	Kondengaden, Shukkoor M..,Luo, Liu-fei.,Huang, Kenneth.,Zhu, Mengyuan.,Zang, Lanlan.,...&Wang, Peng George.(2016).Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,122,382-393.
MLA	Kondengaden, Shukkoor M.,et al."Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 122(2016):382-393.