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Research Articles: Therapeutics

SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity

¹ Pfizer Global Research and Development; ² Phenomix Corp., San Diego, California; ³ Exelixis, Inc.; ⁴ Celera Genomics, Inc., South San Francisco, California; ⁵ Chiron Corp., Emeryville, California; ⁶ The Scripps Research Institute; ⁷ The Burnham Institute, La Jolla, California; ⁸ AstraZeneca PLC, Waltham, Massachusetts; ⁹ Metabolex, Inc., Hayward, California; and ¹⁰ Gilead Sciences, Inc., Foster City, California

Requests for reprints: Dana Hu-Lowe, Pfizer Global Research and Development, 10777 Science Center Drive, San Diego, CA 92024. E-mail: dana.hu-lowe{at}pfizer.com

Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813 inhibited ligand-dependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813 inhibited VEGFR-2, PDGFR-ß, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumor-bearing mice compared with administration of either agent alone. In summary, SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813 in advanced malignancies. [Mol Cancer Ther 2006;5(7):1774–82]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S. Patyna, A.D. Laird, D.B. Mendel, A-M. O'Farrel, C. Liang, H. Guan, T. Vojkovsky, S. Vasile, X. Wang, J. Chen, C.Y. Yang, J.. Haznedar, J. Sukbuntherng, J.M. Cherrington were employees of the former SUGEN Inc., South San Francisco, California, where key portions of the data were generated.

¹¹ Pfizer, Inc., data on file, New York, NY, 2006, unpublished data.

¹² D. Hu-Lowe, in preparation.

Received 8/23/05; revised 4/25/06; accepted 5/ 4/06.

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