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Abstract
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.
Highlights
Vascular endothelial growth factor (VEGF) is involved in tumor angiogenesis and plays an important role in tumor malignancy, such as sustaining tumor growth and in blood-borne metastasis
KRN951 markedly inhibited the ligand-induced phosphorylation of VEGF receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 in the cellular assay (IC50 values 0.16-0.24 nmol/L; Table 1)
It is widely accepted that VEGF signaling through the VEGFR-2 in endothelial cells is primarily responsible for tumor
Summary
Vascular endothelial growth factor (VEGF) is involved in tumor angiogenesis and plays an important role in tumor malignancy, such as sustaining tumor growth and in blood-borne metastasis. VEGF expression is up-regulated by changes associated with cancer, such as hypoxia, proto-oncogene activation, loss of tumor suppressor gene expression, and growth factor stimuli in tumors [1, 2]. Two high-affinity cognate endothelial receptors for VEGF have been identified [8, 9]: VEGF receptor-1 (VEGFR-1; known as Flt-1) and VEGFR-2 [ known as kinase insert domain-containing receptor (KDR)/Flk-1]. Both are members of a large family of receptor tyrosine kinases, and are almost exclusively located in endothelial cells. The affinity of VEGF for VEGFR-1 is higher than for VEGFR2, the major mitogenic, angiogenic, and permeability-enhancing effects of VEGF seem to be mediated through VEGFR-2
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