【摘 要】
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c-MET is a receptor protein-tyrosine kinase whose activating ligand is hepatocyte growth factor/scatter factor (HGF/SF).Because of the critical roles of aberrant signaling in cancer, c-MET is an attra
【机 构】
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Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia, Nanjing, China
【出 处】
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第七届国际分子模拟与信息技术应用学术会议
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c-MET is a receptor protein-tyrosine kinase whose activating ligand is hepatocyte growth factor/scatter factor (HGF/SF).Because of the critical roles of aberrant signaling in cancer, c-MET is an attractive oncology target for therapeutic intervention.Crizotinib(PF-02341066) was used as a reference to search the NCI database and the hits were docked into c-MET kinase domain.The hits were broken into fragments and formed a fragment library using DiscoveryStudio 4.0.Four sub-pockets of c-MET kinase domain, revealed a novel ATP site environment,were separately bounded with small molecules to generate best fragments.Finally, A novel 5-(1H-1,2,3-triazol-4-yl)pyrazin-2-amine series was createdto make the key interactions.After tumor growth inhibition assay in vitro, AM0427 was demonstrated as the most potent which had aIC50 with 60 ±4 nM in cellar level, holding the line with crizotinib.Further optimization of the hit series were generated to improve pharmaceutical properties and the activity toc-MET kinasein vivo.
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