Stabilizers of the interaction between 14-3-3 and hDM2 and hDM

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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.1-3 In turn hDM2 and hDMX function is regulated through phosphorylation dependent interaction with the adaptor protein 14-3-3.4-5 Given that hDM2 and hDMX are overexpressed in numerous cancers, the p53/hDM2(X) interaction has received considerable attention as a drug-discovery target.6This 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. The project will exploit our toolkit of enabling drug discovery capabilities,7-8 in house crystallographic and biophysical data on the nature of the hDM2/14-3-3 and hDMX/14-3-3 interactions together with hit matter identified from conventional screening and dynamic fragment ligation experiments. A range of methods appropriate to the target will be employed including: computational prediction, peptide chemistry, small-molecule synthesis, screening technologies, biophysics and structural-molecular biology. As a collaborative CASE studentship with AstraZeneca, a research placement in Gothenburg will form part of the studentship. This will allow the design, synthesis and testing of candidate PPI stabilizers to discover a selective and cell-permeable modulators.