title: A novel small molecule inhibitor of FAK and IGF-1R protein interactions decreases growth of human esophageal carcinoma.
abstract: BACKGROUND
  Esophageal cancer remains an aggressive disease with poor survival rates. FAK and IGF-1R are two important tyrosine kinases important for cell survival signaling and found to be upregulated in esophageal cancer. Our hypothesis is that a novel small molecule compound that disrupts FAK and IGF-1R protein-protein interactions (PPIs) would decrease the growth of human esophageal cancer.
  
  
  METHODS
  The compound INT2-31 (NSC344553) was identified from a virtual high throughput screen to bind to FAK and disrupt PPIs. The in vitro effects of this compound, +/- 5-FU chemotherapy, on cell signaling, viability and apoptosis in human esophageal cancer cells (KYSE 70, 140) and a direct esophageal cancer xenograft was evaluated.
  
  
  RESULTS
  INT2-31 caused a disruption of PPIs between FAK and IGF-1R starting at a concentration of 1μM. It also caused a dose dependent inhibition of cell viability and induction of apoptosis at low micromolar doses. These effects were associated with decreased AKT and ERK1/ERK2 phosphorylation. INT2-31 treatment, when administered via IP injection, at 50mg/kg, resulted in an in vivo decrease in tumor growth in a direct xenograft. Furthermore, treatment with 5-FU chemotherapy combined with INT2-31 resulted in a synergistic increase in apoptosis and decrease in tumor growth compared to 5-FU or INT2-31 alone.
  
  
  CONCLUSIONS
  A novel compound that disrupts the PPIs of FAK and IGF-1R results in decreased tumor proliferation and increased apoptosis. These effects appear to be mediated through downregulation of p-AKT and p-ERK. This compound deserves further study as a novel treatment strategy in patients with esophageal cancer.
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Deniz A
authors.initials: DA
authors.lastname: Ucar
authors.forename: Audrey
authors.initials: A
authors.lastname: Cox
authors.forename: Di-Hua
authors.initials: DH
authors.lastname: He
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.forename: Elena
authors.initials: E
authors.lastname: Kurenova
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hochwald
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004947:Esophagus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011684:Purine Nucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C577148:4-(methylthio)-7-(5-O-phosphonoribofuranosyl)-7H-pyrrolo(2,3-d)pyrimidine; D047428:Protein Kinase Inhibitors; D011684:Purine Nucleosides; D017526:Receptor, IGF Type 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D005472:Fluorouracil