Mechanism Of Drug Action

We are interested in

  • the use and discovery of small molecules to activate p53 functions in cancer cells
  • the discovery of novel p53-activating drug combinations that are synergistic in action
  • exploring the various distinct signaling pathways leading to p53 activation for therapeutic exploitation
  • the use of small molecules in zebrafish and mouse model systems

Activation of p53

p53 is frequently inactivated in a wide variety of cancers and point mutations or deletions of p53 gene are associated with a poor prognosis in anticancer therapy. Half of all human tumors carry wildtype p53 but p53 wildtype functions are frequently either suppressed by the overexpression of murine double minute 2 (MDM2) or the deletion of Arf. Restoration of p53 functions in tumor cells therefore represents an attractive strategy in combating cancer. Our primary interest is in screening for drug compounds or small molecules that activates p53.

Designed p53 cell-based reporter assays are used in drug compound screening. The simple yet robust assay allows us to assay for p53 activity in the cell in multiple drug dose and timepoints experiments. The validated assay demonstrates a strong correlation between p53 reporter activity and cell cycle arrest and apoptosis mediated in a p53-dependent manner. An additional advantage of such a reporter system is that it allows one to screen for bioactive drug compounds as opposed to general toxic compounds that results in unspecific killing of cells.

Drug combinations

Simultaneously targeting different pathways will be an effective method to achieve synergism in p53 activation. We are exploring novel drug combinations that may provide a way to lower the effective chemotherapeutic drug doses without comprising target endpoint of the drugs.