Discovery of a potent, highly selective Tie-2 kinase inhibitor demonstrating in vivo efficacy, based on a novel pyridyl triazine scaffold.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5549 Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor cell 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 fully understood. In order to explore the therapeutic utility of Tie-2 inhibition we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases critical for tumor angiogenesis. A pyridyl triazine-based inhibitor exhibited >30-fold selectivity, good oral exposure, and in vivo inhibition of Tie-2 autophosphorylation. With the aid of X-ray co-crystal structures, hypotheses about the origin of selectivity over VEGFR-2 and other kinases can begin to be formulated. Classical heterocyclic chemistry and palladium-catalyzed reactions were utilized to rapidly modify this modular scaffold. The identification of potent and highly selective Tie-2 inhibitors with activity in vivo has provided a unique tool to assess the role of Tie-2 signaling in tumor angiogenesis.