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J. Biol. Chem., Vol. 282, Issue 20, 14845-14852, May 18, 2007

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Cellular Characterization of a Novel Focal Adhesion Kinase Inhibitor^*

Jill K. Slack-Davis¹, Karen H. Martin¹, Robert W. Tilghman¹, Marcin Iwanicki, Ethan J. Ung, Christopher Autry, Michael J. Luzzio, Beth Cooper, John C. Kath, W. Gregory Roberts², and J. Thomas Parsons³

From the Department of Microbiology and Cancer Center, Health Sciences System, University of Virginia, Charlottesville, Virginia 22908 and Discovery Oncology, Pfizer Inc., Groton, Connecticut 06340

Focal adhesion kinase (FAK) is a member of a family of non-receptor protein-tyrosine kinases that regulates integrin and growth factor signaling pathways involved in cell migration, proliferation, and survival. FAK expression is increased in many cancers, including breast and prostate cancer. Here we describe perturbation of adhesion-mediated signaling with a FAK inhibitor, PF-573,228. In vitro, this compound inhibited purified recombinant catalytic fragment of FAK with an IC₅₀ of 4 nM. In cultured cells, PF-573,228 inhibited FAK phosphorylation on Tyr³⁹⁷ with an IC₅₀ of 30–100 nM. Treatment of cells with concentrations of PF-573,228 that significantly decreased FAK Tyr³⁹⁷ phosphorylation failed to inhibit cell growth or induce apoptosis. In contrast, treatment with PF-573,228 inhibited both chemotactic and haptotactic migration concomitant with the inhibition of focal adhesion turnover. These studies show that PF-573,228 serves as a useful tool to dissect the functions of FAK in integrin-dependent signaling pathways in normal and cancer cells and forms the basis for the generation of compounds amenable for preclinical and patient trials.

Received for publication, July 14, 2006 , and in revised form, March 13, 2007.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and supplemental Movies S1 and S2.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed for all compound requests. ³To whom correspondence should be addressed: Dept. of Microbiology, University of Virginia, P.O. Box 800734, Jordan Hall, 1300 Jefferson Park Ave., Charlottesville, VA 22908-0734. Tel.: 434-924-5395; Fax: 434-982-1071; E-mail: jtp{at}virginia.edu.

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