TY - JOUR T1 - A Selective and Oral Small Molecule Inhibitor of Vascular Epithelial Growth Factor Receptor (VEGFR)-2 and VEGFR-1 Inhibits Neovascularization and Vascular Permeability JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 838 LP - 845 DO - 10.1124/jpet.103.052167 VL - 306 IS - 3 AU - Neela Patel AU - Li Sun AU - Deborah Moshinsky AU - Hui Chen AU - Kathleen M. Leahy AU - Phuong Le AU - Katherine G. Moss AU - Xueyan Wang AU - Audie Rice AU - Danny Tam AU - A. Douglas Laird AU - Xiaoming Yu AU - Qingling Zhang AU - Cho Tang AU - Gerald McMahon AU - Anthony Howlett Y1 - 2003/09/01 UR - http://jpet.aspetjournals.org/content/306/3/838.abstract N2 - Vascular endothelial growth factor (VEGF) is a key driver of the neovascularization and vascular permeability that leads to the loss of visual acuity in diabetic retinopathy and neovascular age-related macular degeneration. Our aim was to identify an orally active, selective small molecule kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-2 with activity against both VEGF-induced angiogenesis and vascular permeability. We used a biochemical assay to identify 3-[5-methyl-2- (2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-proprionic acid (SU10944), a pyrrole indolinone, which is a potent ATP-competitive inhibitor of VEGFR-2 (Ki of 21 ± 5 nM). In cellular assays, SU10944 inhibited VEGF-induced receptor autophosphorylation (IC50 of 227 ± 80 nM) as well as downstream signaling (IC50 of 102 ± 27 nM). In biochemical assays, SU10944 exhibits potent inhibitory activity against VEGFR-1; weak activity against other related subgroup members, including stem cell factor receptor (SCFR), platelet-derived growth factor receptor β (PDGFRβ), and fibroblast growth factor receptor-1 (FGFR-1); and no detectable activity against other protein tyrosine kinases such as epidermal growth factor receptor (EGFR), Src, and hepatocyte growth factor receptor. In cellular assays, the selectivity for SU10944 to inhibit VEGFR is maintained compared with other tyrosine kinases (IC50 for SCFR of 1.6 ± 0.3 μM, for PDGFRβ of 30.6 ± 13.3 μM, for FGFR-1 of >50 μM, and for EGFR of >50 μM). Upon oral administration, SU10944 gave a clear dose response in the corneal micropocket model with an ED50 value for inhibition of neovascularization of ∼30 mg/kg and a maximum inhibition of 95% at 300 mg/kg. Similarly, upon oral administration in the Miles assay, SU10944 potently inhibited VEGF-induced vascular permeability. Our data indicate that small molecule inhibitors of VEGFR signaling have the potential to ameliorate VEGF-induced neovascularization as well as vascular permeability. The American Society for Pharmacology and Experimental Therapeutics ER -