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SU6668 Is a Potent Antiangiogenic and Antitumor Agent That Induces Regression of Established Tumors¹

SUGEN, Inc., San Francisco, California 94080 [A. D. L., L. K. S., C. L., R. A. B., T. A. T. F., L. M. S., L. S., C. T., R. H., F. T., N. S., K. P. H., G. M., J. M. C.]; Department of Neurosurgery, Klinikum Mannheim, University of Heidelberg, D-68167 Mannheim, Germany [P. V., A. T.]; Department of Pharmacology, New York University Medical Center, New York, New York 10016 [M. M., J. S.]; Department of Molecular Biology, Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany [A. U.]; and Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University Medical Center, New York, New York 10016 [S. R. H.]

Vascular endothelial growth factor, fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their cognate receptor tyrosine kinases are strongly implicated in angiogenesis associated with solid tumors. Using rational drug design coupled with traditional screening technologies, we have discovered SU6668, a novel inhibitor of these receptors. Biochemical kinetic studies using isolated Flk-1, FGF receptor 1, and PDGF receptor ß kinases revealed that SU6668 has competitive inhibitory properties with respect to ATP. Cocrystallographic studies of SU6668 in the catalytic domain of FGF receptor 1 substantiated the adenine mimetic properties of its oxindole core. Molecular modeling of SU6668 in the ATP binding pockets of the Flk-1/KDR and PDGF receptor kinases provided insight to explain the relative potency and selectivity of SU6668 for these receptors. In cellular systems, SU6668 inhibited receptor tyrosine phosphorylation and mitogenesis after stimulation of cells by appropriate ligands. Oral or i.p. administration of SU6668 in athymic mice resulted in significant growth inhibition of a diverse panel of human tumor xenografts of glioma, melanoma, lung, colon, ovarian, and epidermoid origin. Furthermore, intravital multifluorescence videomicroscopy of C6 glioma xenografts in the dorsal skinfold chamber model revealed that SU6668 treatment suppressed tumor angiogenesis. Finally, SU6668 treatment induced striking regression of large established human tumor xenografts. Investigations of SU6668 activity in cancer patients are ongoing in Phase I clinical trials.

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				T. M. J. Niederman, Z. Ghogawala, B. S. Carter, H. S. Tompkins, M. M. Russell, and R. C. Mulligan Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors PNAS, May 14, 2002; 99(10): 7009 - 7014. [Abstract] [Full Text] [PDF]

				A. D. LAIRD, J. G. CHRISTENSEN, G. LI, J. CARVER, K. SMITH, X. XIN, K. G. MOSS, S. G. LOUIE, D. B. MENDEL, and J. M. CHERRINGTON SU6668 inhibits Flk-1/KDR and PDGFR{beta} in vivo, resulting in rapid apoptosis of tumor vasculature and tumor regression in mice FASEB J, May 1, 2002; 16(7): 681 - 690. [Abstract] [Full Text] [PDF]

				R. Beliveau, D. Gingras, E. A. Kruger, S. Lamy, P. Sirois, B. Simard, M. G. Sirois, L. Tranqui, F. Baffert, E. Beaulieu, et al. The Antiangiogenic Agent Neovastat (Ae-941) Inhibits Vascular Endothelial Growth Factor-mediated Biological Effects Clin. Cancer Res., April 1, 2002; 8(4): 1242 - 1250. [Abstract] [Full Text] [PDF]

				M. C. Heinrich, C. D. Blanke, B. J. Druker, and C. L. Corless Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies J. Clin. Oncol., March 15, 2002; 20(6): 1692 - 1703. [Abstract] [Full Text] [PDF]

				C.S. Brock and S.M. Lee Anti-angiogenic strategies and vascular targeting in the treatment of lung cancer Eur. Respir. J., March 1, 2002; 19(3): 557 - 570. [Abstract] [Full Text] [PDF]

				R. J. Griffin, B. W. Williams, R. Wild, J. M. Cherrington, H. Park, and C. W. Song Simultaneous Inhibition of the Receptor Kinase Activity of Vascular Endothelial, Fibroblast, and Platelet-derived Growth Factors Suppresses Tumor Growth and Enhances Tumor Radiation Response Cancer Res., March 1, 2002; 62(6): 1702 - 1706. [Abstract] [Full Text] [PDF]

				T. Itokawa, H. Nokihara, Y. Nishioka, S. Sone, Y. Iwamoto, Y. Yamada, J. Cherrington, G. McMahon, M. Shibuya, M. Kuwano, et al. Antiangiogenic Effect by SU5416 Is Partly Attributable to Inhibition of Flt-1 Receptor Signaling Mol. Cancer Ther., March 1, 2002; 1(5): 295 - 302. [Abstract] [Full Text] [PDF]

				F. Carlomagno, D. Vitagliano, T. Guida, M. Napolitano, G. Vecchio, A. Fusco, A. Gazit, A. Levitzki, and M. Santoro The Kinase Inhibitor PP1 Blocks Tumorigenesis Induced by RET Oncogenes Cancer Res., February 1, 2002; 62(4): 1077 - 1082. [Abstract] [Full Text] [PDF]

				M. Ozen, D. Giri, F. Ropiquet, A. Mansukhani, and M. Ittmann Role of Fibroblast Growth Factor Receptor Signaling in Prostate Cancer Cell Survival J Natl Cancer Inst, December 5, 2001; 93(23): 1783 - 1790. [Abstract] [Full Text] [PDF]

				P. Guo, L. Xu, S. Pan, R. A. Brekken, S.-T. Yang, G. B. Whitaker, M. Nagane, P. E. Thorpe, J. S. Rosenbaum, H.-J. Su Huang, et al. Vascular Endothelial Growth Factor Isoforms Display Distinct Activities in Promoting Tumor Angiogenesis at Different Anatomic Sites Cancer Res., December 1, 2001; 61(23): 8569 - 8577. [Abstract] [Full Text] [PDF]

				R. S. Kerbel Clinical Trials of Antiangiogenic Drugs: Opportunities, Problems, and Assessment of Initial Results J. Clin. Oncol., September 15, 2001; 19(90001): 45s - 51. [Full Text] [PDF]

				G. W. Krystal, S. Honsawek, D. Kiewlich, C. Liang, S. Vasile, L. Sun, G. McMahon, and K. E. Lipson Indolinone Tyrosine Kinase Inhibitors Block Kit Activation and Growth of Small Cell Lung Cancer Cells Cancer Res., May 1, 2001; 61(9): 3660 - 3668. [Abstract] [Full Text]

				Y. Yamasaki, K. Miyoshi, N. Oda, M. Watanabe, H. Miyake, J. Chan, X. Wang, L. Sun, C. Tang, G. McMahon, et al. Weekly Dosing With the Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor SU9518 Significantly Inhibits Arterial Stenosis Circ. Res., March 30, 2001; 88(6): 630 - 636. [Abstract] [Full Text] [PDF]

				B. D. Smolich, H. A. Yuen, K. A. West, F. J. Giles, M. Albitar, and J. M. Cherrington The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts Blood, March 1, 2001; 97(5): 1413 - 1421. [Abstract] [Full Text] [PDF]

				R. M. Shaheen, W. W. Tseng, D. W. Davis, W. Liu, N. Reinmuth, R. Vellagas, A. A. Wieczorek, Y. Ogura, D. J. McConkey, K. E. Drazan, et al. Tyrosine Kinase Inhibition of Multiple Angiogenic Growth Factor Receptors Improves Survival in Mice Bearing Colon Cancer Liver Metastases by Inhibition of Endothelial Cell Survival Mechanisms Cancer Res., February 1, 2001; 61(4): 1464 - 1468. [Abstract] [Full Text]

				D. B. Mendel, R. E. Schreck, D. C. West, G. Li, L. M. Strawn, S. S. Tanciongco, S. Vasile, L. K. Shawver, and J. M. Cherrington The Angiogenesis Inhibitor SU5416 Has Long-lasting Effects on Vascular Endothelial Growth Factor Receptor Phosphorylation and Function Clin. Cancer Res., December 1, 2000; 6(12): 4848 - 4858. [Abstract] [Full Text]