Development and biological evaluation of small molecule inhibitors for Met using a new strategy

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Met tyrosine kinase transduces multifunctional signals that enhance tumor progression, invasion, and angiogenesis. Also Met correlates well with poor prognosis in clinical cancers. Therefore, Met is considered to be a suitable molecule for targeting therapy. Introducing our new strategy named COSMOS (Conversion to Small Molecules through Optimized-Peptides Strategy), we have designed candidate molecules for Met inhibitors. Main strategic concept of the drug design for Met was based on its similarity to the tertiary structure of T315I-mutated type Bcr-Abl. Among various molecules tested, two compounds inhibited Met kinase activity most effectively, thereby showing the possibility of becoming candidate lead compounds. We also developed oligopeptides that can bind Met kinase and effectively inhibits its activity. These results provide information about a new strategy for developing small molecule inhibitors for Met.