Discovery of a new series of imidazo1,2-apyridine compounds as selective c-Met inhibitors

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	Discovery of a new series of imidazo1,2-apyridine compounds as selective c-Met inhibitors
其他题名	Discovery of a new series of imidazo1,2-apyridine compounds as selective c-Met inhibitors
	Liu Tongchao 1; Peng Xia 2; Ma Yuchi 2; Ji Yinchun 2; Chen Danqi 2; Zheng Mingyue 2; Zhao Dongmei 1; Cheng Maosheng 1; Geng Meiyu 2; Shen Jingkang 2; Ai Jing 2; Xiong Bing 2
	2016
发表期刊	ACTA PHARMACOLOGICA SINICA
ISSN	1671-4083
卷号	37 期号:5 页码:698-707
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.
其他摘要	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-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.
关键词	RECEPTOR TYROSINE KINASE INVASIVE GROWTH SCATTER FACTOR CANCER DOCKING c-Met inhibitors hepatocyte growth factor receptor imidazo1,2-apyridine anticancer agents drug discovery
收录类别	CSCD
语种	英语
资助项目	[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记录号	CSCD:5700554
引用统计
文献类型	期刊论文
条目标识符	http://ir.imr.ac.cn/handle/321006/148382
专题	中国科学院金属研究所
作者单位	1.中国科学院金属研究所 2.中国科学院
推荐引用方式 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.