title: Disruption of focal adhesion kinase and p53 interaction with small molecule compound R2 reactivated p53 and blocked tumor growth.
abstract: BACKGROUND
  Focal Adhesion Kinase (FAK) is a 125 kDa non-receptor kinase that plays a major role in cancer cell survival and metastasis.
  
  
  METHODS
  We performed computer modeling of the p53 peptide containing the site of interaction with FAK, predicted the peptide structure and docked it into the three-dimensional structure of the N-terminal domain of FAK involved in the complex with p53. We screened small molecule compounds that targeted the site of the FAK-p53 interaction and identified compounds (called Roslins, or R compounds) docked in silico to this site.
  
  
  RESULTS
  By different assays in isogenic HCT116p53+/+ and HCT116 p53-/- cells we identified a small molecule compound called Roslin 2 (R2) that bound FAK, disrupted the binding of FAK and p53 and decreased cancer cell viability and clonogenicity in a p53-dependent manner. In addition, dual-luciferase assays demonstrated that the R2 compound increased p53 transcriptional activity that was inhibited by FAK using p21, Mdm-2, and Bax-promoter targets. R2 also caused increased expression of p53 targets: p21, Mdm-2 and Bax proteins. Furthermore, R2 significantly decreased tumor growth, disrupted the complex of FAK and p53, and up-regulated p21 in HCT116 p53+/+ but not in HCT116 p53-/- xenografts in vivo. In addition, R2 sensitized HCT116p53+/+ cells to doxorubicin and 5-fluorouracil.
  
  
  CONCLUSIONS
  Thus, disruption of the FAK and p53 interaction with a novel small molecule reactivated p53 in cancer cells in vitro and in vivo and can be effectively used for development of FAK-p53 targeted cancer therapy approaches.
authors.forename: Vita M
authors.initials: VM
authors.lastname: Golubovskaya
authors.forename: Baotran
authors.initials: B
authors.lastname: Ho
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Andrew
authors.initials: A
authors.lastname: Magis
authors.forename: David
authors.initials: D
authors.lastname: Ostrov
authors.forename: Carl
authors.initials: C
authors.lastname: Morrison
authors.forename: William G
authors.initials: WG
authors.lastname: Cance
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D054852:Small Molecule Libraries; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D051417:Focal Adhesion Kinase 1; D005472:Fluorouracil