Cellular characterization of a novel focal adhesion kinase inhibitor

J Biol Chem. 2007 May 18;282(20):14845-52. doi: 10.1074/jbc.M606695200. Epub 2007 Mar 28.


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 IC(50) of 4 nM. In cultured cells, PF-573,228 inhibited FAK phosphorylation on Tyr(397) with an IC(50) of 30-100 nM. Treatment of cells with concentrations of PF-573,228 that significantly decreased FAK Tyr(397) 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.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemotaxis / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Heterocyclic Compounds, 4 or More Rings / chemistry*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Heterocyclic Compounds, 4 or More Rings / therapeutic use
  • Humans
  • Male
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / enzymology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Quinolones / chemistry*
  • Quinolones / pharmacology*
  • Signal Transduction / drug effects*
  • Sulfones / chemistry*
  • Sulfones / pharmacology*


  • 6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one
  • Heterocyclic Compounds, 4 or More Rings
  • Protein Kinase Inhibitors
  • Quinolones
  • Sulfones
  • Focal Adhesion Protein-Tyrosine Kinases