Activity-directed discovery of ATP-competitive probes of Nek7 kinase biology

This project will focus on the discovery of ATP-competitive inhibitors of NEK (Never in Mitosis A-related kinase) family kinases, and their exploitation to investigate the cellular functions of NEKs. High quality chemical probes can address the highly unsystematic historic exploration of the biology of proteins e.g. which protein kinases are investigated.
A fragment-based discovery approach will be exploited to drive the discovery of novel inhibitors. Activity-directed synthesis (ADS) – a discovery approach that has recently been realised in Leeds – will drive the fragment-based discovery of novel NEK inhibitors. Crucially, ADS can identify productive strategies for fragment elaboration even in the absence of structural information. The structural basis of the novel NEK inhibitors will be determined by protein crystallography. The resulting chemical probes will be exploited to investigate the cellular NEK function, for example in mediating mitotic spindle assembly.