Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search
文献类型：期刊论文
| 作者 | Ding, Hong1,2 ; Lu, Wen Chao2; Hu, Jun Chi2; Liu, Yu-Chih3; Zhang, Chen Hua3; Lian, Fu Lin2; Zhang, Nai Xia2; Meng, Fan Wang2,4; Luo, Cheng2; Chen, Kai Xian1,2
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| 刊名 | MOLECULES
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| 出版日期 | 2018-03 |
| 卷号 | 23期号:3 |
| 关键词 | SET7 inhibitor similarity search ligand-based drug design chemical biology probe |
| ISSN号 | 1420-3049 |
| DOI | 10.3390/molecules23030567 |
| 文献子类 | Article |
| 英文摘要 | SET7, serving as the only histone methyltransferase that monomethylates 'Lys-4' of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What's more, SET7 is involved in the pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC50 = 9.3 mu M). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification of DC-S303 with the IC50 value of 1.1 mu M. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 mu M), Jurkat (IC50 = 2.2 mu M), THP1 (IC50 = 3.5 mu M), U937 (IC50 = 3.9 mu M) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compound DC-S239. What's more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology. |
| WOS关键词 | LYSINE METHYLTRANSFERASE ; DRUG DISCOVERY ; POSTTRANSLATIONAL MODIFICATIONS ; SET9-MEDIATED METHYLATION ; TRANSCRIPTIONAL ACTIVITY ; EPIGENETIC MODIFICATIONS ; CELL-PROLIFERATION ; ENDOTHELIAL-CELLS ; GENOTOXIC STRESS ; ACCURATE DOCKING |
| 资助项目 | Ministry of Science and Technology of China (National Key R&D Program of China)[2017YFB0202600] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81430084] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000428514100058 |
| 出版者 | MDPI |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279861]  |
| 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 分析化学研究室 |
| 通讯作者 | Meng, Fan Wang; Chen, Kai Xian |
| 作者单位 | 1.Shanghai Univ Tradit Chinese Med, Sch Pharm, 1200 Cailun Rd, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.Shanghai ChemPartner Co Ltd, 5 Bldg,998 Halei Rd, Shanghai 201203, Peoples R China; 4.McMaster Univ, Dept Chem & Chem Biol, 1280 Main St West, Hamilton, ON L8S 4L8, Canada |
| 推荐引用方式 GB/T 7714 | Ding, Hong,Lu, Wen Chao,Hu, Jun Chi,et al. Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search[J]. MOLECULES,2018,23(3). |
| APA | Ding, Hong.,Lu, Wen Chao.,Hu, Jun Chi.,Liu, Yu-Chih.,Zhang, Chen Hua.,...&Chen, Kai Xian.(2018).Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search.MOLECULES,23(3). |
| MLA | Ding, Hong,et al."Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search".MOLECULES 23.3(2018). |
入库方式： OAI收割
来源：上海药物研究所
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