title: Influence of novel KGFR tyrosine kinase inhibitors on KGF-mediated proliferation of breast cancer.
abstract: BACKGROUND
  Keratinocyte growth factor (KGF) acts at the KGF receptor (KGFR) to produce a rapid stimulation of breast cancer cell proliferation and motility which is mediated via the Erk signaling pathway. Enhancement of KGF/KGFR signal transduction may be an early step in the metastatic progression of breast cancer. Receptor modeling of KGFR was used to identify selective KGFR tyrosine kinase (TK) inhibitor molecules that have the potential to bind selectively to the KGFR. The present study evaluated the biological activity of 57 of these KGFR TK inhibitor compounds on breast cancer cells.
  
  
  METHODS
  These compounds were tested for their ability to inhibit KGF-mediated breast cancer cell proliferation in MCF-7 breast cancer cells. Furthermore, the effects of the most effective proliferation inhibitors were examined on Erk signaling and on the relative density of cell membrane KGFR.
  
  
  RESULTS
  It was observed that 27 of the 57 compounds tested produced a 20% or greater reduction in KGF-mediated proliferation; while five compounds produced greater than 50% inhibition. In addition, the most potent inhibitors also reduced Erk signaling and cell membrane density of the KGFR.
  
  
  CONCLUSIONS
  The compounds examined appear to be selective KGFR inhibitors which inhibit KGF-mediated activity and reduce the expression of KGFR on cancer cells. These results may lead to the development of a novel class of anticancer agents for the prevention of metastatic cancer progression.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
authors.forename: Meghna
authors.initials: M
authors.lastname: Mehta
authors.forename: Jason W
authors.initials: JW
authors.lastname: Kesinger
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zang
authors.forename: Megan L
authors.initials: ML
authors.lastname: Lerner
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brackett
authors.forename: Robert W
authors.initials: RW
authors.lastname: Brueggemeier
authors.forename: Pui-Kui
authors.initials: PK
authors.lastname: Li
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Pento
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D051523:Fibroblast Growth Factor 7; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor; D048049:Extracellular Signal-Regulated MAP Kinases