Targeted Protein Degradation

PROTAC^®-mediated degradation of a target provides many advantages to traditional occupancy-based inhibition by small molecules. Degraders developed from leads, warheads, or inhibitors demonstrate improved cellular responses and target selectivity. As the degrader is not eliminated alongside the target, it is recycled, operating catalytically at lower doses. Lastly, where ~80% of protein targets have been deemed intractable to traditional small molecules due to a lack of defined binding cavities or active sites (“undruggables”), lower affinity binders have been successfully developed into successful degraders by their ability to recruit diverse targets to an E3 ligase. Due in part to these reasons, protein degraders have been identified as new modalities in drug discovery and hold a promising future as research tools.

As protein degraders interact with both a target protein and E3 ligase simultaneously, their design is not trivial. A modular approach is often taken to generate PROTAC^® libraries to screen for degradation of target proteins. To do this, strategic permutations of E3 ligands, target warheads, and linkers are synthesized with growing attention to linker properties and exit vectors. Each member of the target-specific degrader library is analyzed for depletion of the target in cells, providing leads for further optimization and characterization.

PROTAC^® is a registered trademark of Arvinas Operations, Inc., and is used under license.