Inhibition of angiogenesis may have wide use in the treatment of
cancer; however, this approach alone will not cause
tumor regression but may only slow the growth of solid
tumors. The clinical potential of
antiangiogenic agents may be increased by combining them with conventional chemotherapeutics. 4-[4-(1-Amino-1-methylethyl)phenyl]-2-[4-(2-morpholin-4-yl-ethyl)phenylamino]
pyrimidine-5-carbonitrile (JNJ-17029259) represents a novel structural class of 5-cyanopyrimidines that are orally available, selective, nanomolar inhibitors of the
vascular endothelial growth factor receptor-2 (VEGF-R2) and other
tyrosine kinases involved in angiogenesis, such as
platelet-derived growth factor receptor,
fibroblast growth factor receptor, VEGF-R1, and VEGF-R3, but have little activity on other
kinase families. At nanomolar levels,
JNJ-17029259 blocks
VEGF-stimulated
mitogen-activated protein kinase signaling, proliferation/migration, and VEGF-R2 phosphorylation in human endothelial cells; inhibits the formation of vascular sprouting in the rat aortic ring model of angiogenesis; and interferes with the development of new veins and arteries in the chorioallantoic membrane assay. At higher concentrations of 1 to 3 microM, this compound shows antiproliferative activity on cells that may contribute to its antitumor effects.
JNJ-17029259 delays the growth of a wide range of human
tumor xenografts in nude mice when administered orally as single-agent
therapy. Histological examination revealed that the
tumors have evidence of reduced vascularity
after treatment. In addition,
JNJ-17029259 enhances the effects of the conventional chemotherapeutic drugs
doxorubicin and
paclitaxel in xenograft models when administered orally in combination
therapy. An orally available
angiogenesis inhibitor that can be used in conjunction with standard chemotherapeutic agents to augment their activity may have therapeutic benefit in stopping the progression of
cancer and preventing
metastasis.