An on-protein covalent fragment growth platform for PPIs

Covalent inhibitors can provide a powerful means to target challenging ‘undruggable’ targets such as PPIs. A covalent warhead coupled with a specificity element can exploit a suitably located nucleophilic residue. However, progress from a covalent fragment to a selective covalent inhibitor is an enormous task. This project will develop a new platform technology to accelerate the progression of simple covalent fragments to early tool molecules and expedite hit to lead, using the target protein to template the growth of the fragment. This project has broad multidisciplinary elements in developing a new platform strategy for the discovery of covalent inhibitors, involving organic synthesis, kinetic profiling, protein biochemistry, labelling and screening.