Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening
文献类型：期刊论文
| 作者 | Meng, Fanwang2,3; Cheng, Sufang4; Ding, Hong3 ; Liu, Shien3; Liu, Yan3; Zhu, Kongkai3; Chen, Shijie3; Lu, Junyan3; Xie, Yiqian3; Li, Linjuan1,3
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 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. |
| 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 |
| 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研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000363915600019 |
| 出版者 | AMER CHEMICAL SOC |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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