Synthesis and Evaluation of Targeted Covalent Enzyme Inhibitors in Cancer

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This position will start in October 2019 to work under the supervision of Dr Matthias Baud in the School of Chemistry at the University of Southampton. This project will be at the interface of the chemical and biological sciences, and will focus on the development of new types of mild covalent agents as inhibitors or a range of high-profile disease driving proteins. Targeted covalent Inhibitors (TCIs) are protein ligands containing a reactive chemical "warhead" able to create a covalent bond with the protein target. Targeted covalent inhibition of key disease associated proteins is a rapidly growing area of drug discovery. It is a powerful way to increase the potency and/or selectivity of small molecule inhibitors by allowing the covalent, irreversible association of a reactive warhead to specific sites of proteins. The candidate will focus on the design and synthesis of TCIs functionalised with new types of mild reactive warheads currently under investigation in our laboratory, along with the evaluation of their bioactivity using in-house in vitro assays. We are particularly interested in the application of these methodologies for 1) improving the selectivity profile of inhibitors across structurally related proteins, 2) along with addressing the challenging issues of drug resistance originating from mutations in cancer.