An orally bioavailable amino-triazole compound that is shown to bind to the inactive conformations of both PDGFRb and Raf kinases (allosteric, Type II inh), and acts as a potent inhibitor of Flt3, Kit, PDGFRa and PDGFRb (=52, 170, 300 and 520nM, respectively) with selectivity over B-Raf, p38a, FGFR2 and VEGFR2 (>10uM) in a multi-kinase panel. Completely blocks the phosphorylations of MEK-1/2 S217/S221, ERK-1/2 T202/Y204 in FGF-stimulated HUVECs, PDGFRb in PDGF-BB-stimulated VSMCs, ERK-1/2 T202/Y204 in 1205Lu-B Raf V600E cells, and C-Raf S338 at 10uM. Reduces FGF-induced angiogenesis in mouse Matrigel model (50mg/kg, i.p., bid) and selectively induces apoptosis in the endothelium; further, suppresses orthotopic renal cell carcinoma growth in mice (100mg/kg, p.o., qd).
Storage and Stability:Lyophilized powder may be stored at -20°C. Stable for 12 months at -20°C. Reconstitute with sterile buffer or dH2O. Aliquot to avoid repeated freezing and thawing. Store at -20°C. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap. Further dilutions can be made in assay buffer.
