Received for publication March 28, 2003.
Revised April 16, 2003.
Accepted for publication May 14, 2003.

A Selective and Oral Small Molecule Inhibitor of VEGFR-2 and VEGFR-1 Inhibits Neovascularization and Vascular Permeability

Abstract

Vascular epithelial growth factor (VEGF) is a key driver of the neovascularization and vascular permeability which lead 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 VEGFR-2 with activity against both VEGF-induced angiogenesis and vascular permeability. We utilized a biochemical assay to identify SU10944, a pyrrole indolinone, which is a potent ATP- competitive inhibitor of VEGFR-2 (K_i 21 ±5 nM). In cellular assays SU10944 inhibited VEGF- induced receptor autophosphorylation (IC₅₀ 227&plusmn]80 nM) as well as downstream signaling (IC₅₀ 102±27 nM). In biochemical assays SU10944 exhibits potent inhibitory activity against VEGFR-1, weak activity against other related subgroup members including SCF-R, PDGFR , and FGFR- 1, and no detectable activity against other protein tyrosine kinases such as EGFR, Src, and HGFR. In cellular assays the selectivity for SU10944 to inhibit VEGFR is maintained compared to other tyrosine kinases (IC₅₀ SCF-R 1.6±0.3 uM, PDGFR 30.6±13.3 uM, FGFR-1>50 uM, EGFR>50 uM). Upon oral administration, SU10944 gave a clear dose response in the corneal micropocket model with an ED₅₀ 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 both VEGF induced neovascularization as well as vascular permeability.

Key words: SU10944, VEGFR-1, VEGFR-2, angiogenesis, kinase inhibitor, vascular permeability

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