Design, Synthesis, and Biological Evaluation of the First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives
文献类型：期刊论文
| 作者 | Lu, Dong2,3; Yan, Juan1,3; Wang, Lang2; Liu, Hongchun1 ; Zeng, Limin2; Zhang, Minmin1; Duan, Wenwen2; Ji, Yinchun1; Cao, Jingchen1; Geng, Meiyu1
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| 刊名 | ACS MEDICINAL CHEMISTRY LETTERS
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| 出版日期 | 2017-08 |
| 卷号 | 8期号:8页码:830-834 |
| 关键词 | Dual c-Met/HDAC inhibitor hybrid designed multiple ligand (DML) |
| ISSN号 | 1948-5875 |
| DOI | 10.1021/acsmedchemlett.7b00172 |
| 文献子类 | Article |
| 英文摘要 | Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, 2m, inhibited c-Met kinase and HDAC1, with IC50 values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound 2m inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule. |
| WOS关键词 | HISTONE DEACETYLASE INHIBITORS ; HDAC INHIBITORS ; CANCER CELLS ; KINASE ; PATHWAY ; GROWTH ; LINES ; ACID |
| 资助项目 | National Natural Science Foundation of China[81225022] ; National Natural Science Foundation of China[81321092] ; National Natural Science Foundation of China[81673472] ; National Natural Science Foundation of China[81402966] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020105] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000407656800008 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272540]  |
| 专题 | 药理学第一研究室 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 药物化学研究室 |
| 通讯作者 | Shen, Aijun; Hu, Youhong |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lu, Dong,Yan, Juan,Wang, Lang,et al. Design, Synthesis, and Biological Evaluation of the First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives[J]. ACS MEDICINAL CHEMISTRY LETTERS,2017,8(8):830-834. |
| APA | Lu, Dong.,Yan, Juan.,Wang, Lang.,Liu, Hongchun.,Zeng, Limin.,...&Hu, Youhong.(2017).Design, Synthesis, and Biological Evaluation of the First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives.ACS MEDICINAL CHEMISTRY LETTERS,8(8),830-834. |
| MLA | Lu, Dong,et al."Design, Synthesis, and Biological Evaluation of the First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives".ACS MEDICINAL CHEMISTRY LETTERS 8.8(2017):830-834. |
入库方式： OAI收割
来源：上海药物研究所
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