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Discovery of a new series of imidazo1,2-apyridine compounds as selective c-Met inhibitors
Alternative TitleDiscovery 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 PublicationACTA PHARMACOLOGICA SINICA
ISSN1671-4083
Volume37Issue:5Pages:698-707
AbstractAim: 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 AbstractAim: 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.
KeywordRECEPTOR TYROSINE KINASE INVASIVE GROWTH SCATTER FACTOR CANCER DOCKING c-Met inhibitors hepatocyte growth factor receptor imidazo1,2-apyridine anticancer agents drug discovery
Indexed ByCSCD
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 IDCSCD:5700554
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Document Type期刊论文
Identifierhttp://ir.imr.ac.cn/handle/321006/148385
Collection中国科学院金属研究所
Affiliation1.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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