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Beschreibung

"A cell-permeable anthranilamide that acts as a potent VEGFR inhibitor (IC50 = 130, 23, and 18 nM against VEGFR-1, -2, and -3, respectively, IC50 = 1.24 nM against VEGF-induced human VEGFR-2 phosphorylation in CHO cells) by targeting the ATP-binding site of VEGFR in its inactive ""DFG-out"" conformation, while inhibiting c-kit, CSF-1R/c-Fms, PDGFR-beta, and c-Abl only at higher concentrations (IC50 = 236, 380, 640, and 2820 nM, respectively) and displaying little or no activity against EGFR/HER-1/ErbB (IC50 = 10.4 M) and six other kinases (IC50 >=10 M). Reported to be orally available in mice (Conc. in plasma = 9.5, 4.7, 1.5, and 1.1 M, respectively, 0.5 h, 1 h, 1.5 h, and 2 h after p.o. dosage of 50 mg/kg), rats, and dogs, and effectively suppress tumor growths (50 to 100 mg/kg, p.o.) via its anti-angiogenesis activity in various cancer models in vivo, including murine melanoma B16-BL6, rat mammary adenocarcinoma BN472, as well as human prostate cancer DU145-grafted mice in vivo. AAL933 and two other VEGFR inhibitors, KRN633 and SU5416, are also shown to inhibit hypoxia- (1% O2) induced HIF-1alpha expression (by <90% at 30 M) and transcription activation (IC50 = 6.53, 3.79, and 8.24 M, respectively, by AAL933, KRN633, and SU5416 in HeLa-HRE-Luc reporter assays). However, unlike KRN633 and SU5416, AAL933 prevents only hypoxia-induced Erk, but not Akt, phosphorylation in HeLa cells., A cell-permeable anthranilamide that acts as a potent VEGFR inhibitor (IC50 = 130, 23, and 18 nM against VEGFR-1, -2, and -3, respectively, IC50 = 1.24 nM against VEGF-induced human VEGFR-2 phosphorylation in CHO cells) by targeting the ATP-binding site of VEGFR in its inactive ""DFG-out"" conformation and effectively suppresses tumor growths (50 to 100 mg/kg, p.o.) via its anti-angiogenesis activity in mice and rats in vivo, while inhibiting c-kit, CSF-1R/c-Fms, PDGFR-beta, and c-Abl only at higher concentrations (IC50 = 236, 380, 640, and 2820 nM, respectively). AAL933 and two other VEGFR inhibitors, KRN633 and SU5416, are also shown to inhibit hypoxia-induced HIF-1alpha expression (by <90% at 30 M) and transcription activation. Unlike KRN633 and SU5416, AAL933 prevents only hypoxia-induced Erk, but not Akt, phosphorylation in HeLa cells."