An Antitumor 2-Hydroxyarylidene-4-cyclopentene-1,3-Dione as a Protein Tyrosine Kinase Inhibitor: Interaction Between TX-1123 Derivatives and Src Kinase

Protein tyrosine kinases (PTKs) play major roles in signal transduction during cell proliferation and apoptosis. Tyrphostin AG17 was previously shown to be a potent tumor growth inhibitor, while AG17 induced apoptosis and inhibited activity of cyclin-dependent kinase 2. We herein describe the binding features of tyrphostin AG17 analogs, such as TX-1123, with Src kinase (Src-K).Structural data for Src-K were obtained from a protein data bank (ID=2SRC), and the molecular interactions between Src-K and TX-1123 derivatives were examined.TX-1123 exihibited potent Src-K inhibitory activity (half maximal-inhibitory concentration=2.2 μM), and fit into the pocket of the Src-K molecule as well as c-AMP did.The binding profiles of TX-1123 derivatives differed from each other, while their Src-K inhibitory activities were affected by their fit in the Src-K molecule.