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CELLULAR AND MOLECULAR

A Selective and Oral Small Molecule Inhibitor of Vascular Epithelial Growth Factor Receptor (VEGFR)-2 and VEGFR-1 Inhibits Neovascularization and Vascular Permeability

Sugen, Inc., South San Francisco, California (N.P., L.S., D.M., H.C., P.L, K.G.M., X.W., A.R., D.T., A.D.L., X.Y., Q.Z., C.T., G.M., A.H.); and Pharmacia Corporation, Chesterfield, Missouri (K.M.L.)

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 (K_i 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 (PDGFR), 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 PDGFR 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.

Address correspondence to: Dr. Neela Patel, Discovery Biology, Sugen, Inc., 230 E. Grand Ave., South San Francisco, CA 94080. E-mail: neela.patel{at}sugen.com

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