OSI-930

OSI-930 is a dual inhibitor of Kit (IC₅₀s = 80 and 629 nM for the activated and non-activated kinase, respectively, in cell-free assays) and VEGFR2 (IC₅₀ = 9 nM).¹ It is selective for these kinases over a panel of 17 additional kinases (IC₅₀s = 1.3->10 µM) but also inhibits VEGFR1, CSF1R, C-RAF, and LCK (IC₅₀s = 8, 15, 41, and 22 nM, respectively). OSI-930 inhibits Kit autophosphorylation in NCI-H526 and HMC-1 cells expressing wild-type Kit and Kit containing the constitutively active V560G mutation (Kit^V560G), respectively, and stem cell factor-induced Kit autophosphorylation in NCI-H526 cells expressing wild-type Kit (IC₅₀s = 58.1 and 78.9 nM, respectively). It also inhibits VEGF-induced autophosphorylation of VEGFR2 in human umbilical vein endothelial cells (HUVECs; IC₅₀ = 64.4 nM). OSI-930 (100 nM) decreases endothelial sprout formation by greater than 50% in isolated rat aortic rings. It reduces tumor growth in a variety of mouse xenograft models, including colon and small-cell lung cancer, melanoma, and glioblastoma models, when administered orally at a dose of 200 mg/kg per day.

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1. Garton, A.J., Crew, A.P.A., Franklin, M.C., et al. OSI-930: A novel selective inhibitor of kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res. 66(2), 1015-1024 (2006).