Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor

TLDR

Angiogenesis inhibition is a clinically validated strategy for limiting tumor growth, and the Tie‑2 receptor tyrosine kinase, expressed almost exclusively in vascular endothelium, is essential for developmental angiogenesis and vessel maturation, yet its role in tumor angiogenesis remains unclear. The study aimed to assess the therapeutic potential of Tie‑2 inhibition by developing potent, orally bioavailable small‑molecule inhibitors with high selectivity over other kinases involved in tumor angiogenesis. These inhibitors were designed from X‑ray co‑crystal structures of KDR inhibitors, yielding a potent, nonselective Tie‑2 inhibitor (pyridinyl pyrimidine 6) that served as a scaffold for further optimization toward selectivity over other angiogenesis‑related kinases. Lead optimization produced pyridinyl triazine 63, which showed more than 30‑fold selectivity over a kinase panel, favorable oral exposure, and effective in vivo inhibition of Tie‑2 phosphorylation.

Abstract

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 KDR 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.