Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009;12(3):287-96.
doi: 10.1007/s10456-009-9151-7. Epub 2009 Jun 21.

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

Kenneth R LaMontagne  1 , Jeannene Butler, Virna B Borowski, Angel R Fuentes-Pesquera, Jonathan M Blevitt, Shenlin Huang, Ronghua Li, Peter J Connolly, Lee M Greenberger
Affiliations

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

Kenneth R LaMontagne et al. Angiogenesis. 2009.

Abstract

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 microM) 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.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

MeSH terms

Substances

LinkOut - more resources