Stabilizers of the interaction between 14-3-3 and hDM2/hDMX

Transient protein-protein interactions (PPIs) control all cellular processes relevant to health and disease. Selective modulation of individual PPIs would thus facilitate both a greater understanding of biological mechanisms and provide new opportunities for therapeutic intervention. p53 is a critical tumour suppressor involved in DNA repair, inhibition of cell proliferation and cell cycle regulation. P53 is negatively regulated through interaction with hDM2 and/or hDMX. These proteins regulate localization of p53, physically block its interaction with DNA and act in concert to effect p53 degradation through ubiquitination and subsequent proteolytic degradation. In turn hDM2 and hDMX function is regulated through phosphorylation dependent interaction with the adaptor protein 14-3-3. Given that hDM2 and hDMX are overexpressed in numerous cancers, the p53/hDM2(X) interaction has received considerable attention as a drug-discovery target. This PhD project will pursue an alternative approach to target the oncogenic p53 pathway by identification and optimization of stabilizers of hDM2/14-3-3 and hDMX/14-3-3.

Applications will be considered on an ongoing basis. Due to funding restrictions, the position must be awarded as soon as possible. Potential applicants are strongly encouraged to contact the supervisors for an informal discussion before making a formal application. We also advise that you apply at the earliest opportunity as the application and selection process may close early, should a suitable candidate be appointed.