KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 18; pp. 9134 - 9142
• Main Authors: NAKAMURA, Kazuhide, TAGUCHI, Eri, SUZUKI, Rika, KUBO, Kinya, SHIBUYA, Masabumi, ISOE, Toshiyuki, MIURA, Toru, YAMAMOTO, Atsushi, TAKAHASHI, Kazumi, BICHAT, Francis, GUILBAUD, Nicolas, HASEGAWA, Kazumasa, KUBO, Kazuo, FUJIWARA, Yasunari
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-09-2006
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological and medical sciences; Capillary Permeability - drug effects; Cell Line, Tumor; Endothelial Cells - drug effects; Endothelial Cells - physiology; Humans; Isoxazoles - pharmacokinetics; Isoxazoles - pharmacology; Magnetic Resonance Imaging; Medical sciences; Mice; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - metabolism; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; NIH 3T3 Cells; Pharmacology. Drug treatments; Phenylurea Compounds - pharmacokinetics; Phenylurea Compounds - pharmacology; Phosphorylation; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Random Allocation; Rats; Rats, Nude; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Signal Transduction - drug effects; Tumors; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Xenograft Model Antitumor Assays; Antineoplastic agent; Vascular endothelium growth factor; Blood vessel; Receptor tyrosine kinase; Inhibitor; Circulatory system; Biological activity
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-4290

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.