VEGFR Tyrosine Kinase Inhibitor VI, AAL-993

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-β, 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-1α 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.

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-β, 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-1α 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.

Packaged under inert gas

Toxicity: Regulatory Review (Z)

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Ban, H.S., et al. 2010. Cancer Lett.296, 17; Manley, P.W., et al. 2004. Biochim. Biophys. Acta1697, 17; Manley, P.W., et al. 2002. J. Med. Chem.45, 5687.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany