Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity
文献类型：期刊论文
| 作者 | Zhan, Zhengsheng1; Ai, Jing2 ; Liu, Qiufeng3; Ji, Yinchun2; Chen, Tiantian3; Xu, Yechun3; Geng, Meiyu2; Duan, Wenhu1
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| 刊名 | ACS MEDICINAL CHEMISTRY LETTERS
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| 出版日期 | 2014-06 |
| 卷号 | 5期号:6页码:673-678 |
| 关键词 | Anilinopyrimidine dual inhibitor c-Met SAR VEGFR-2 |
| ISSN号 | 1948-5875 |
| DOI | 10.1021/ml500066m |
| 文献子类 | Article |
| 英文摘要 | Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 mu M. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues. |
| WOS关键词 | PROGNOSTIC INDICATOR ; NUCLEAR ACCUMULATION ; ONCOGENE ADDICTION ; TYROSINE KINASE ; TUMOR-GROWTH ; ANGIOGENESIS ; METASTASIS ; OVEREXPRESSION ; CABOZANTINIB ; CARCINOMA |
| 资助项目 | National Natural Science Foundation of China[81273365] ; National Natural Science Foundation of China[81102461] ; Major Projects in National Science and Technology of China[2010ZX09401-401] ; Major Projects in National Science and Technology of China[2012ZX09103101-024] ; Major Projects in National Science and Technology of China[2012ZX09301001-007] ; National Program on Key Basic Research Project of China[2012CB910704] ; "100 Talents Project" of CAS[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000337497200014 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277044]  |
| 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 药物化学研究室 药理学第一研究室 |
| 通讯作者 | Xu, Yechun |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, 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 |
| 推荐引用方式 GB/T 7714 | Zhan, Zhengsheng,Ai, Jing,Liu, Qiufeng,et al. Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity[J]. ACS MEDICINAL CHEMISTRY LETTERS,2014,5(6):673-678. |
| APA | Zhan, Zhengsheng.,Ai, Jing.,Liu, Qiufeng.,Ji, Yinchun.,Chen, Tiantian.,...&Duan, Wenhu.(2014).Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity.ACS MEDICINAL CHEMISTRY LETTERS,5(6),673-678. |
| MLA | Zhan, Zhengsheng,et al."Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity".ACS MEDICINAL CHEMISTRY LETTERS 5.6(2014):673-678. |
入库方式： OAI收割
来源：上海药物研究所
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