A novel small molecule inhibitor of FAK decreases growth of human pancreatic cancer

Cell Cycle. 2009 Aug;8(15):2435-43. doi: 10.4161/cc.8.15.9145. Epub 2009 Aug 1.

Abstract

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that is overexpressed in many types of tumors, including pancreatic cancer, and plays an important role in cell adhesion and survival signaling. Pancreatic cancer is a lethal disease and is very resistant to chemotherapy, and FAK has been shown recently to assist in tumor cell survival. Therefore, FAK is an excellent potential target for anti-cancer therapy. We identified a novel small molecule inhibitor (1,2,4,5-Benzenetetraamine tetrahydrochloride, that we called Y15) targeting the main autophosphorylation site of FAK and hypothesized that it would be an effective treatment strategy against human pancreatic cancer. Y15 specifically blocked phosphorylation of Y397-FAK and total phosphorylation of FAK. It directly inhibited FAK autophosphorylation in a dose- and time-dependent manner. Furthermore, Y15 increased pancreatic cancer cell detachment and inhibited cell adhesion in a dose-dependent manner. Y15 effectively caused human pancreatic tumor regression in vivo, when administered alone and its effects were synergistic with gemcitabine chemotherapy. This was accompanied by a decrease in Y397-phosphorylation of FAK in the tumors treated with Y15. Thus, targeting the Y397 site of FAK in pancreatic cancer with the small molecule inhibitor, 1,2,4,5-Benzenetetraamine tetrahydrochloride, is a potentially effective treatment strategy in this deadly disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Synergism
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Gemcitabine
  • Humans
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms / enzymology*
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Kinase Inhibitors / toxicity
  • Xenograft Model Antitumor Assays

Substances

  • 1,2,4,5-benzenetetraamine
  • Aniline Compounds
  • Protein Kinase Inhibitors
  • Deoxycytidine
  • Focal Adhesion Protein-Tyrosine Kinases
  • Gemcitabine