Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations
文献类型：期刊论文
| 作者 | Tao, Hongrui1,3; Yan, Xue3; Zhu, Kongkai2; Zhang, Hua2 |
| 刊名 | CHEMICAL & PHARMACEUTICAL BULLETIN
 |
| 出版日期 | 2019-04-01 |
| 卷号 | 67期号:4页码:382-388 |
| 关键词 | virtual screening epigenetic inhibitor antiproliferation molecular docking |
| ISSN号 | 0009-2363 |
| 通讯作者 | Zhu, Kongkai(hkhhh.k@163.com) ; Zhang, Hua(bio_zhangh@ujn.edu.cn) |
| 英文摘要 | As an important epigenetics related enzyme, protein arginine methyltransferase 5 (PRMT5) has been confirmed as an anticancer therapeutic target in recent years. Among all the reported PRMT5 inhibitors, two small molecules (GSK-3326595 and JNJ-64619178) are currently being assessed in clinical trial. In this study, 40 PRMT5 inhibitor candidates were purchased from SPECS database supplier according to the pharmacophore and molecular docking based virtual screening results. Alpha linked immunosorbent assay (LISA) methylation assay was performed to test their inhibitory activity against PRMT5. The in vitro enzymatic assay results indicated that four compounds (2, 4, 10 and 37) showed PRMT5 inhibitory activity, while 4 and 10 displayed the most potent activity with IC50 values of 8.1 +/- 1.1 and 6.5 +/- 0.6 mu M, respectively. The inhibitory activity results of 20 extra analogs of 4 further confirmed the potency of this scaffold. As expected, compounds 4 and 10 exhibited moderate anti -proliferative activity against mantle cell lymphoma Jeko-1 and leukemia cell MV4-11. Besides, Western blot assay results showed that 4 could reduce the H4R3me2s level in a dose-dependent manner, indicating that it could inhibit the activity of PRMT5 in cellular context. Detailed interactions between 4 and PRMT5 were characterized by binding mode analysis through molecular docking. The compounds discovered in this study will inspire medicinal chemists to further explore this series of PRMT5 inhibitors. |
| WOS关键词 | ARGININE METHYLTRANSFERASE 5 ; SMALL-MOLECULE INHIBITORS ; SELECTIVE INHIBITOR ; IDENTIFICATION ; POTENT ; OPTIMIZATION ; METHYLATION ; DOCKING ; DESIGN ; GROWTH |
| 资助项目 | National Natural Science Foundation of China[81803438] ; Shandong Provincial Natural Science Foundation[JQ201721] ; Shandong Provincial Natural Science Foundation[ZR2017BH038] ; Young Taishan Scholars Program[tsqn20161037] ; Shandong Talents Team Cultivation Plan of University Preponderant Discipline[10027] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000463466000015 |
| 出版者 | PHARMACEUTICAL SOC JAPAN |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/289964]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhu, Kongkai; Zhang, Hua |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 2.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China 3.Univ Jinan, Sch Chem & Chem Engn, Jinan 250022, Shandong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tao, Hongrui,Yan, Xue,Zhu, Kongkai,et al. Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations[J]. CHEMICAL & PHARMACEUTICAL BULLETIN,2019,67(4):382-388. |
| APA | Tao, Hongrui,Yan, Xue,Zhu, Kongkai,&Zhang, Hua.(2019).Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations.CHEMICAL & PHARMACEUTICAL BULLETIN,67(4),382-388. |
| MLA | Tao, Hongrui,et al."Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations".CHEMICAL & PHARMACEUTICAL BULLETIN 67.4(2019):382-388. |
入库方式： OAI收割
来源：上海药物研究所
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