Vita M Golubovskaya, Baotran Ho, Min Zheng, Andrew Magis, David Ostrov, Carl Morrison and William G Cance
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.
Keywords: Focal adhesion kinase, p53Cancer, Small molecule, p21, Tumor, Apoptosis
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