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First published on June 10, 2004; DOI: 10.1124/mol.104.000638

0026-895X/04/6603-635-647$20.00
Mol Pharmacol 66:635-647, 2004

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A Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor Potentiates the Activity of the Conventional Chemotherapeutic Agents Paclitaxel and Doxorubicin in Tumor Xenograft Models

Stuart Emanuel, Robert H. Gruninger, Angel Fuentes-Pesquera, Peter J. Connolly, Jennifer A. Seamon, Susan Hazel, Rose Tominovich, Beth Hollister, Cheryl Napier, Michael R. D'Andrea, Michael Reuman, Gilles Bignan, Robert Tuman, Dana Johnson, David Moffatt, Mark Batchelor, Anne Foley, James O'Connell, Rodger Allen, Martin Perry, Linda Jolliffe, and Steven A. Middleton

Cancer Therapeutics Research (S.E., R.H.G., A. F.-P., P.J.C., J.A.S., M.R., G.B., L.J., S.A.M.) and Oncology Research (R.To., M.R.D., R.Tu., D.J.], Johnson & Johnson Pharmaceutical Research and Development, Raritan, New Jersey; Institute of Medical and Veterinary Science, Adelaide, Australia (S.H.); Piedmont Research Center, Morrisville, North Carolina (B.H., C.N.); and Celltech Research, Limited, Slough, United Kingdom (D.M., M.B., A.F., J.O., R.A., M.P.)

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 µM, 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.

Received for publication March 19, 2004.

Accepted for publication June 9, 2004.

Address correspondence to: Dr. Stuart Emanuel, Johnson and Johnson Pharmaceutical Research and Development, LLC, 1000 Route 202, Raritan, NJ 08869. E-mail: semanuel{at}prdus.jnj.com




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