The Development of Multifunctional p53 Reactivators for Cancer Therapy

The p53 protein plays a major role in cancer prevention, and over 50% of cancer diagnoses can be attributed to mutated p53. The main function of p53 is to prevent uncontrolled growth of damaged cells and inhibit tumour formation. Mutant p53 has provided a unique opportunity to design multifunctional molecules that act on different aspects of mutant p53 simultaneously for increased chemotherapeutic efficacy. Incorporation of a zinc metallochaperone (ZMC) scaffold has been vital in the restoration of mutant p53. However, many ZMCs have been shown to generate intracellular reactive oxygen species (ROS) through Fenton-like chemistry by chelating redox-active metals like Fe and Cu. The generation of ROS can lead to significant off-target toxicity. The key purpose of this research project is to tune the Zn-affinity of new multifunctional p53 reactivators to minimize off-target effects by substituting an acid-based chelator and it is hypothesized that the acid-based chelator will promote preferential binding to Zn over other endogenous metals.

Faculty Supervisor:

Tim Storr

Student:

Partner:

Université de Strasbourg

Discipline:

Life Sciences

Sector:

Education

University:

Simon Fraser University

Program: