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

• Published in: The Journal of pharmacology and experimental therapeutics 2003-09, Vol.306 (3), p.838-845
• Main Authors: Patel, Neela, Sun, Li, Moshinsky, Deborah, Chen, Hui, Leahy, Kathleen M, Le, Phuong, Moss, Katherine G, Wang, Xueyan, Rice, Audie, Tam, Danny, Laird, A Douglas, Yu, Xiaoming, Zhang, Qingling, Tang, Cho, McMahon, Gerald, Howlett, Anthony
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Capillary Permeability - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Indoles - pharmacology; Indoles - therapeutic use; Mice; Neovascularization, Pathologic - prevention & control; Propionates - pharmacology; Propionates - therapeutic use; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.052167

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)-1 H -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 (IC 50 of 227 ± 80 nM) as well as downstream signaling (IC 50 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 (IC 50 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 ED 50 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.