Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors
文献类型：期刊论文
| 作者 | Liu, Tong-chao1,2; Peng, Xia3; Ma, Yu-chi1; Ji, Yin-chun3; Chen, Dan-qi1 ; Zheng, Ming-yue1; Zhao, Dong-mei2; Cheng, Mao-sheng2; Geng, Mei-yu3; Shen, Jing-kang1
|
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2016-05 |
| 卷号 | 37期号:5页码:698-707 |
| 关键词 | c-Met inhibitors hepatocyte growth factor receptor imidazo[1,2-a]pyridine anticancer agents drug discovery |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2016.11 |
| 文献子类 | Article |
| 英文摘要 | Aim: Aberrant c-Met activation plays a critical role in cancer formation, progression and dissemination, as well as in development of resistance to anticancer drugs. Therefore, c-Met has emerged as an attractive target for cancer therapy. The aim of this study was to develop new c-Met inhibitors and elaborate the structure-activity relationships of identified inhibitors. Methods: Based on the predicted binding modes of Compounds 5 and 14 in docking studies, a new series of c-Met inhibitor-harboring 3-((1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)imidazo[1,2-a]pyridine scaffolds was discovered. Potent inhibitors were identified through extensive optimizations combined with enzymatic and cellular assays. A promising compound was further investigated in regard to its selectivity, its effects on c-Met signaling, cell proliferation and cell scattering in vitro. Results: The most potent Compound 31 inhibited c-Met kinase activity with an IC50 value of 12.8 nmol/L, which was >78-fold higher than those of a panel of 16 different tyrosine kinases. Compound 31 (8, 40, 200 nmol/L) dose-dependently inhibited the phosphorylation of c-Met and its key downstream Akt and ERK signaling cascades in c-Met aberrant human EBC-1 cancer cells. In 12 human cancer cell lines harboring different background levels of c-Met expression/activation, Compound 31 potently inhibited c-Met-driven cell proliferation. Furthermore, Compound 31 dose-dependently impaired c-Met-mediated cell scattering of MDCK cells. Conclusion: This series of c-Met inhibitors is a promising lead for development of novel anticancer drugs. |
| WOS关键词 | RECEPTOR TYROSINE KINASE ; ANTITUMOR-ACTIVITY ; COLORECTAL-CANCER ; INVASIVE GROWTH ; SCATTER FACTOR ; CELLS ; METASTASIS ; MOTILITY ; DOCKING |
| 资助项目 | Foundation of China Postdoctoral Science[00000000] ; National Natural Science Foundation of China[81202391] ; National Natural Science Foundation of China[91229205] ; National Natural Science Foundation of China[81473243] ; National Natural Science Foundation of China[81321092] ; National Natural Science Foundation of China[81330076] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2014ZX09507002] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2012ZX09301001-007] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2013ZX09507001] ; SA-SIBS Scholarship Program[00000000] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5700554 |
| WOS记录号 | WOS:000375415600013 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276056]  |
| 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 药物化学研究室 |
| 通讯作者 | Zhao, Dong-mei; Ai, Jing; Xiong, Bing |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai 201203, Peoples R China; 2.Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, Shenyang 110016, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Tong-chao,Peng, Xia,Ma, Yu-chi,et al. Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2016,37(5):698-707. |
| APA | Liu, Tong-chao.,Peng, Xia.,Ma, Yu-chi.,Ji, Yin-chun.,Chen, Dan-qi.,...&Xiong, Bing.(2016).Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors.ACTA PHARMACOLOGICA SINICA,37(5),698-707. |
| MLA | Liu, Tong-chao,et al."Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors".ACTA PHARMACOLOGICA SINICA 37.5(2016):698-707. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。