Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines
文献类型：期刊论文
| 作者 | Kondengaden, Shukkoor M.1,2; Luo, Liu-fei3; Huang, Kenneth1,2; Zhu, Mengyuan1,2; Zang, Lanlan1,2,4; Bataba, Eudoxie1,2; Wang, Runling4; Luo, Cheng5 ; Wang, Binghe1,2; Li, Keqin Kathy1,2,3
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 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. |
| WOS关键词 | PLURIPOTENT STEM-CELLS ; HISTONE METHYLTRANSFERASE ; DNA METHYLATION ; CHEMICAL PROBE ; GLP ; H3 ; TRIMETHYLATION ; SUV39H1 ; ANALOGS ; GENES |
| 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研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000383003900032 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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