Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor

Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase TIE-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of TIE-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting TIE-2 signaling, we developed a series of potent and orally bioavailable small molecule TIE-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective TIE-2 inhibitor that was designed on the basis of X-ray cocrystal structures of VEGFR2/KDR/Flk-1 inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of TIE-2 phosphorylation.