Vascular endothelial growth factor (
VEGF) plays a key role in
tumor angiogenesis by stimulating the proangiogenic signaling of endothelial cells via activation of
VEGF receptor (VEGFR)
tyrosine kinases. Therefore, VEGFRs are an attractive therapeutic target for
cancer treatment. In the present study, we show that a
quinoline-
urea derivative,
KRN951, is a novel
tyrosine kinase inhibitor for VEGFRs with antitumor angiogenesis and antigrowth activities.
KRN951 potently inhibited
VEGF-induced
VEGFR-2 phosphorylation in endothelial cells at in vitro subnanomolar IC50 values (IC50 = 0.16 nmol/L). It also inhibited
ligand-induced phosphorylation of
platelet-derived growth factor receptor-
beta (PDGFR-beta) and c-Kit (IC50 = 1.72 and 1.63 nmol/L, respectively).
KRN951 blocked
VEGF-dependent, but not
VEGF-independent, activation of
mitogen-activated protein kinases and proliferation of endothelial cells. In addition, it inhibited
VEGF-mediated migration of human umbilical vein endothelial cells. Following p.o. administration to athymic rats,
KRN951 decreased the microvessel density within
tumor xenografts and attenuated
VEGFR-2 phosphorylation levels in
tumor endothelium. It also displayed antitumor activity against a wide variety of human
tumor xenografts, including lung, breast, colon, ovarian, pancreas, and
prostate cancer. Furthermore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis revealed that a significant reduction in
tumor vascular hyperpermeability was closely associated with the antitumor activity of
KRN951. These findings suggest that
KRN951 is a highly potent, p.o. active antiangiogenesis and
antitumor agent and that DCE-MRI would be useful in detecting early responses to
KRN951 in a clinical setting.
KRN951 is currently in phase I clinical development for the treatment of patients with advanced
cancer.