Fragment Based Drug Design of Novel Pyrazine Derivates Inhibiting Mesenchymal Epithelial Transition Factor (c-MET) Kinase
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.
c-MET kinase FBDD Crizotinib
Xin Xue
Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia, Nanjing, China
国内会议
苏州
英文
196-200
2014-10-26（万方平台首次上网日期，不代表论文的发表时间）