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Bioorg Med Chem. 2011 Sep 15;19(18):5342-51. doi: 10.1016/j.bmc.2011.08.002. Epub 2011 Aug 6.

Biochemical characterization of a novel type-II VEGFR2 kinase inhibitor: comparison of binding to non-phosphorylated and phosphorylated VEGFR2.

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Discovery Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-chome, Fujisawa, Kanagawa 251-8555, Japan.


A pyrrolo[3,2-d]pyrimidine-based type-II vascular endothelial growth factor receptor 2 (VEGFR2) kinase inhibitor, compound 20d, displayed time-dependent inhibition of the non-phosphorylated catalytic domain of VEGFR2. In contrast, 20d did not show time-dependent inhibition of the phosphorylated enzyme. Dissociation of 20d from non-phosphorylated VEGFR2 was slow and the half-life of the complex was longer than 4h. In contrast, dissociation of 20d from the phosphorylated enzyme was very fast (half-life <5min). A fluorescent tracer based displacement assay and surface plasmon resonance (SPR) analysis confirmed the slow dissociation of 20d from only non-phosphorylated VEGFR2. Thus, activity based and binding kinetic analyses both supported slow dissociation of 20d from only non-phosphorylated VEGFR2. Additionally SPR analysis revealed that association rates were rapid and nearly identical for these two phosphorylation forms of VEGFR2. From these results, the preferential effect of 20d on non-phosphorylated VEGFR2 is dominated by its slow dissociation from the enzyme and this characteristically long residence time may increase its potency in vivo. The present findings may assist in the design of novel type-II kinase inhibitors.

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