High-throughput discovery of lysine-directed probes for protein kinases

The resurgence of covalent drug discovery has yielded FDA-approved drugs in therapeutic areas as diverse as cancer, virology and sickle cell anaemia. Irreversible inhibitors usually target a nucleophilic cysteine, a strategy whose success relies on the presence of a suitable residue that is not susceptible to mutation. In the case of the protein kinases, the conserved lysine residue that is intimately involved in phosphotransfer provides a major and undertapped opportunity for the discovery of new drugs and chemical probes. 

In this project, we will harness a high-throughput approach to discover covalent probes that target the conserved lysine in protein kinases. The student will develop plate-based chemistry in which pairs of building blocks will be combined to yield diverse probe sets. The probe sets will be exploited to discover novel covalent modifiers of specific protein kinases. The student will harness a chemical proteomic approach to profile the proteome-wide reactivity of the discovered probes; and exploit biochemical and structural biology approaches to characterise their mechanism of action. 

The studentship will take advantage of the outstanding research environment of the Astbury Centre for Structural Molecular Biology, including cutting-edge structural biology and chemical proteomics capabilities.

The specific objectives of the project will be:

1. To develop high-throughput chemistry to enable the synthesis of diverse lysine-directed kinase probes
2. To harness high-throughput experimentation to discover novel covalent modifiers of specific protein kinases
3. To characterise the mechanism of discovered probes using chemical proteomic, biochemical and structural biology approaches.