Vascular endothelial growth factor (
VEGF) and its receptor
VEGFR-2 play a central role in angiogenesis, which is necessary for solid
tumors to expand and metastasize. Specific inhibitors of
VEGFR-2 tyrosine kinase are therefore thought to be useful for treating
cancer. We showed that the
quinazoline urea derivative
KRN633 inhibited
tyrosine phosphorylation of
VEGFR-2 (IC50 = 1.16 nmol/L) in human umbilical vein endothelial cells. Selectivity profiling with recombinant
tyrosine kinases showed that
KRN633 was highly selective for
VEGFR-1, -2, and -3.
KRN633 also blocked the activation of
mitogen-activated protein kinases by
VEGF, along with human umbilical vein endothelial cell proliferation and tube formation. The propagation of various
cancer cell lines in vitro was not inhibited by
KRN633. However, p.o. administration of
KRN633 inhibited
tumor growth in several in vivo
tumor xenograft models with diverse tissue origins, including lung, colon, and prostate, in athymic mice and rats.
KRN633 also caused the regression of some well-established
tumors and those that had regrown after the
cessation of treatment. In these models, the trough serum concentration of
KRN633 had a more significant effect than the maximum serum concentration on antitumor activity.
KRN633 was well tolerated and had no significant effects on
body weight or the general health of the animals. Histologic analysis of
tumor xenografts treated with
KRN633 revealed a reduction in the number of endothelial cells in non-necrotic areas and a decrease in vascular permeability. These data suggest that
KRN633 might be useful in the treatment of solid
tumors and other diseases that depend on
pathologic angiogenesis.