A highly selective, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor has potent activity in vitro and in vivo

• Published in: Angiogenesis (London) Vol. 12; no. 3; pp. 287 - 296
• Main Authors: LaMontagne, Kenneth R., Butler, Jeannene, Borowski, Virna B., Fuentes-Pesquera, Angel R., Blevitt, Jonathan M., Huang, Shenlin, Li, Ronghua, Connolly, Peter J., Greenberger, Lee M.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.09.2009; Springer; Springer Nature B.V
• Subjects: Administration, Oral; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacology; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood and lymphatic vessels; Blood vessels and receptors; Cancer Research; Cardiology; Cardiology. Vascular system; Cell Biology; Cell Movement - drug effects; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - drug effects; Endothelial Cells - physiology; Female; Fundamental and applied biological sciences. Psychology; HCT116 Cells; Humans; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Models, Biological; Neoplasms - drug therapy; Neoplasms - pathology; Oncology; Ophthalmology; Original Paper; Oximes - administration & dosage; Oximes - pharmacology; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Substrate Specificity; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vertebrates: cardiovascular system; Xenograft Model Antitumor Assays; Vascular endothelial growth factor receptor-2; Tryosine kinase inhibitor; Anti-angiogenesis; Angiogenesis; Growth factor receptor; Enzyme; Transferases; Oral administration; Cardiovascular disease; Protein-tyrosine kinase; Biological activity
• DOI: 10.1007/s10456-009-9151-7
• ISSN: 0969-6970

Angiogenesis is a complex process that relies on a variety of growth factors and signaling pathways to stimulate endothelial cell responses and establish functional blood vessels. Signaling through the vascular endothelial growth factor (VEGF) receptors is an important mediator of angiogenesis, a hallmark of tumor growth and metastasis. Inhibition of signaling through VEGF has been clinically validated with FDA-approvals of bevacizumab, sorafenib, and suntinib. Our goal was to discover an orally available, selective VEGFR-2 inhibitor. A novel oxime, 1-{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-yloxy]-2-chloro-phenyl}-3-ethyl-urea (JNJ-38158471), was identified as a potent and selective inhibitor of VEGFR-2. While JNJ-38158471 shares some structure features with sorafenib, unlike sorafenib, it lacks Raf kinase activity. JNJ-38158471 inhibits VEGFR-2 (IC50 = 40 nM) and closely related tyrosine kinases, Ret (180 nM) and Kit (500 nM); it has no significant activity (>1 μM) against VEGFR-1 and VEGFR-3. At nanomolar levels, it inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay and inhibits VEGF-dependent endothelial migration. Once-daily oral dosing of JNJ-3815871 to nude mice bearing human A431, HCT116, and A375 tumors resulted in up to 90% tumor growth inhibition. Strikingly, after termination of JNJ-38158471 monotherapy-treatment of A375 xenografts, tumor growth delay was significantly prolonged up to 4 weeks. Anti-tumor efficacy correlated well with the observed dose concentrations (on a mg/kg basis) necessary to inhibit VEGF-induced corneal angiogenesis in C57BL/6J mice. In addition, the compound inhibited spontaneous polyp formation in the APC min-mouse model. These data demonstrate that JNJ-38158471 is a well tolerated, orally available, highly selective VEGFR-2 inhibitor that may have therapeutic benefit in human malignancies.