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.