Identification of novel EZH2 inhibitors through pharmacophore-based virtual screening and biological assays
文献类型：期刊论文
| 作者 | Wu, Yunlong2; Hu, Junchi3,4; Ding, Hong3 ; Chen, Limin5; Zhang, Yuanyuan3; Liu, Rongfeng1; Xu, Pan3,4; Du, Daohai3; Lu, Wenchao3,4; Liu, Jingqiu3
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
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| 出版日期 | 2016-08-01 |
| 卷号 | 26期号:15页码:3813-3817 |
| 关键词 | EZH2 Epigenetics PRC2 Computational drug design Pharmacophore-based virtual screening |
| ISSN号 | 0960-894X |
| DOI | 10.1016/j.bmcl.2016.05.018 |
| 文献子类 | Article |
| 英文摘要 | Polycomb repressive complex 2 (PRC2) acts as a primary writer for di- and tri-methylation of histone H3 at lysine 27. This protein plays an essential role in silencing gene expression. Enhancer of zeste 2 (EZH2), the catalytic subunit of PRC2, is considered as a promising therapeutic target for cancer. GSK126, a specific inhibitor of EZH2, is undergoing phase I trials for hypermethylation-related cancers. In addition, many derivatives of GSK126 are also commonly used in laboratory investigations. However, studies on the mechanism and drug development of EZH2 are limited by the absence of structural diversity of these inhibitors because they share similar SAM-like scaffolds. In this study, we generated a pharmacophore model based on reported EZH2 inhibitors and performed in silico screenings. Experimental validations led to the identification of two novel EZH2 inhibitors, DCE_42 and DCE_254, with IC50 values of 23 and 11 mu M, respectively. They also displayed significant anti-proliferation activity against lymphoma cell lines. Thus, we discovered potent EZH2 inhibitors with novel scaffold using combined in silico screening and experimental study. Results from this study can also guide further development of novel specific EZH2 inhibitors. (C) 2016 Elsevier Ltd. All rights reserved. |
| WOS关键词 | DE-NOVO DESIGN ; DRUG DESIGN ; STEM-CELLS ; 3D QSAR ; METHYLATION ; DISCOVERY ; METHYLTRANSFERASES ; COMPLEXES ; LYMPHOMA ; STRATEGY |
| 资助项目 | Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[91229204] ; National Science and Technology Major Project 'Key New Drug Creation and Manufacturing Program'[2014ZX09507002] ; Computer Network Information Center[00000000] ; Chinese Academy of Sciences[00000000] ; Shanghai Supercomputing Center[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000380574100083 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275943]  |
| 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 | Zhang, Jin; Yao, Zhiyi; Luo, Cheng |
| 作者单位 | 1.Shanghai ChemPartner Co Ltd, Zhangjiang Hi Tech Pk, Shanghai 201203, Peoples R China; 2.Shanghai Inst Technol, Coll Chem & Environm Engn, Shanghai 210418, Peoples R China; 3.Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 5.Nanchang Univ, Affiliated Hosp 1, Ctr Med Expt, Nanchang 330006, Jiangxi, Peoples R China; 6.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Urol, Shanghai 200127, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wu, Yunlong,Hu, Junchi,Ding, Hong,et al. Identification of novel EZH2 inhibitors through pharmacophore-based virtual screening and biological assays[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2016,26(15):3813-3817. |
| APA | Wu, Yunlong.,Hu, Junchi.,Ding, Hong.,Chen, Limin.,Zhang, Yuanyuan.,...&Luo, Cheng.(2016).Identification of novel EZH2 inhibitors through pharmacophore-based virtual screening and biological assays.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,26(15),3813-3817. |
| MLA | Wu, Yunlong,et al."Identification of novel EZH2 inhibitors through pharmacophore-based virtual screening and biological assays".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 26.15(2016):3813-3817. |
入库方式： OAI收割
来源：上海药物研究所
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