| Discovery of a new series of imidazo1,2-apyridine compounds as selective c-Met inhibitors | |
| Alternative Title | Discovery of a new series of imidazo1,2-apyridine compounds as selective c-Met inhibitors |
| Liu Tongchao1; Peng Xia2; Ma Yuchi2; Ji Yinchun2; Chen Danqi2; Zheng Mingyue2; Zhao Dongmei1; Cheng Maosheng1; Geng Meiyu2; Shen Jingkang2; Ai Jing2; Xiong Bing2 | |
| 2016 | |
| Source Publication | ACTA PHARMACOLOGICA SINICA
 |
| ISSN | 1671-4083 |
| Volume | 37Issue:5Pages:698-707 |
| Abstract | 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. |
| Other Abstract | 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-pyrrolo3,2-cpyridin-1-yl）sulfonyl）imidazo1,2-apyridine 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 ICso 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. |
| Keyword | RECEPTOR TYROSINE KINASE INVASIVE GROWTH SCATTER FACTOR CANCER DOCKING c-Met inhibitors hepatocyte growth factor receptor imidazo1,2-apyridine anticancer agents drug discovery |
| Indexed By | CSCD |
| Language | 英语 |
| Funding Project | [Foundation of China Postdoctoral Science] ; [National Natural Science Foundation of China] ; [National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China] ; [SA-SIBS Scholarship Program] |
| CSCD ID | CSCD:5700554 |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://ir.imr.ac.cn/handle/321006/148382 |
| Collection | 中国科学院金属研究所 |
| Affiliation | 1.中国科学院金属研究所 2.中国科学院 |
| Recommended Citation GB/T 7714 | Liu Tongchao,Peng Xia,Ma Yuchi,et al. Discovery of a new series of imidazo1,2-apyridine compounds as selective c-Met inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2016,37(5):698-707. |
| APA | Liu Tongchao.,Peng Xia.,Ma Yuchi.,Ji Yinchun.,Chen Danqi.,...&Xiong Bing.(2016).Discovery of a new series of imidazo1,2-apyridine compounds as selective c-Met inhibitors.ACTA PHARMACOLOGICA SINICA,37(5),698-707. |
| MLA | Liu Tongchao,et al."Discovery of a new series of imidazo1,2-apyridine compounds as selective c-Met inhibitors".ACTA PHARMACOLOGICA SINICA 37.5(2016):698-707. |
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