BFH772 is an inhibitor of VEGF receptor 2 (VEGFR2; IC50 = 0.0027 μM for the human receptor). It is selective for human VEGFR2 over mouse VEGFR2 and human VEGFR1 and VEGFR3 (IC50s = 1.5, 1.7, and 1.1 μM, respectively), as well as 40-fold selective over B-RAF, RET, and Tie2. BFH772 inhibits VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs; IC50 = <0.01 nM). It inhibits VEGF-induced increases in tissue weight and Tie2 levels in an angiogenesis chamber implant model in mice when administered at doses of 1 and 3 mg/kg per day. BFH772 (3 mg/kg per day) inhibits primary tumor and metastasis growth in a B16 melanoma mouse model.
bfh772 was highly effective at targeting vegfr2 kinase, however, lost 500-fold potency on flk-1, flt-1, and flt-4. bfh772 also targeted b-raf, ret, and tie-2, albeit with at least 40-fold lower potency. bfh772 inhibited the ligand induced autophosphorylation of ret, pdgfr, and kit kinases. bfh772 was selective against the kinases of egfr, erbb2, ins-r, and igf-1r and against the cytoplasmic bcr-abl kinase [1].
the dose response curves of bfh772 at 0.3, 1, and 3 mg/kg showed that even at the lowest concentrations, this naphthalene-1-carboxamide inhibited vegf induced tissue weight and tie-2 levels but only reached statistical significance at 1 mg/kg and above. moreover, bfh772 at 3 mg/kg orally dosed once per day could potently inhibit melanoma growth (54-90% for primary tumor and 71-96% for metastasis tumor) when compared with control ratios [1].
[1] bold g, et al. a novel potent oral series of vegfr2 inhibitors abrogate tumor growth by inhibiting angiogenesis. j med chem. 2016 jan 14;59(1):132-46.
[2] http://adisinsight. springer.com/trials/700244037
