Understanding and Manipulating the Protein-Protein Interactions of Aurora A Kinase using Chemical Biology approaches

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Chemical probes are unique in that they can in a dose and time dependent manner modulate protein function. They can be used to understand the relevance of a protein to a disease process and as starting points for drug discovery. Whilst methods to identify inhibitors of protein-protein interactions (PPI) are becoming established, methods to target PPIs involving intrinsically disordered regions (IDRs) are not well developed. This project will develop enabling physical sciences methods - specifically exploiting covalent protein labelling - to characterize, inhibit and track the intracellular interactions of intrinsically disordered proteins focusing on interactions of the Aurora A Kinase with N-MYC, TPX-2 and TACC3. Aurora A plays an essential role in the cells life-cycle e.g. in cell-division, a process that becomes defective in cancer making it a focus of anticancer drug discovery efforts.Its aims and objectives The CASE studentship with LifeArc will build on extensive preliminary structural data to (i) understand the affects of pre-organise peptidomimetic modulators of Aurora A PPIs, (ii) exploit dynamic ligation screening to identify peptide-small molecule hybrid modulators of Aurora A PPIs and (iii) design covalent chemical probes with new reactive warheads for in cell Aurora A Labelling. The student will gain skills in synthesis, peptide/protein chemistry and biophysics and through collaboration with the project partner (i) gain technical competences in ligand discovery methods (ii) develop a translation mindset.Potential applications and benefitsDevelopment of these tools will address a lack of physical sciences approaches to identify chemical probes for IDRs and reveal insight on the functional role of key regulators of the Aurora A kinase to reveal alternative therapeutic strategies. Modulating PPIs is critical to future healthcare innovation and treatment of multiple diseases with huge societal burdens, e.g. cancer, inflammatory diseases etc. Pursuing this research will thus contribute to the EPSRC prosperity outcomes: Healthy Nation and 21st Century products.