INHIBITING THE MDM2-p53 INTERACTION
Overseen by Prof Martin Noble, Prof Jane Endicott and Dr Jim McDonnell
One focus of my D.Phil. was the inhibition of the interaction between the tumour suppressor p53 and its antagonist MDM2 using small molecules. P53 is the cell’s major tumour suppressor and is tightly controlled by its main antagonist, the proto-oncogene MDM2. During carcinogenesis, the disruption of p53’s function is a significant event, which can be achieved through elevated levels of MDM2. In these cancer types, wild-type p53 fails to carry out its function as a tumour suppressor, which is the essential step towards the development of malignant cells. Thus, inhibiting the MDM2/p53 interaction is a promising target for cancer drug development in these cases, as releasing wild-type p53 would enable the tumour suppressor to resume its native function, triggering apoptosis in the affected cells. We are currently investigating a new class of small molecules designed to disrupt the MDM2-p53 interaction, developed at the University of Newcastle. By gaining insights into the binding of these inhibitors to MDM2, we are aiming to provide the basis for improving the specificity and affinity of inhibition, with the ultimate aim of delivering a candidate for clinical trials.