A discovery platform for novel bifunctional probes and molecular glues

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Traditional small molecule drugs and chemical probes achieve their effect through stoichiometric binding of their protein targets, with the majority modulating just four protein classes. Much of the proteome is currently considered 'undruggable', leaving a clear need for new modalities that manipulate protein function through mechanisms which do not depend on tight binding to a conventional druggable pocket. Effector-driven pharmacology has emerged as a revolutionary approach to impact protein function, exemplified by bifunctional proteolysis-targeting chimeras (PROTACS) and molecular glues (>£10 billion sales in 2020). The drug induces ternary complex formation between a target protein of interest (POI) and an effector protein, often an enzyme, which acts catalytically on the POI to trigger a specific cellular effect. The potential of effector-recruiting drugs to modulate protein function is currently limited by the lack of general approaches to discover new bifunctionals/glues. This project will develop a platform for de novo discovery of these entities leveraging massive encoded molecular libraries, novel covalent ligand screening technologies, synthetic chemistry and chemical biology.