Targeted Protein Degradation

Targeted protein degradation (TPD) is a novel drug discovery strategy that eradicates problem proteins from cells by hijacking cellular degradation processes with small molecules. One of these processes is the ubiquitin-proteasome pathway, an intracellular quality control mechanism that utilizes E3 ubiquitin ligases and associated partners to seek out damaged or misfolded proteins for degradation via the proteasome or “cellular trash can.” Proteolysis-targeting chimeras (PROTAC^® degraders) are heterobifunctional molecules containing a disease target warhead and E3 ligase ligand tethered together by a linker.

When added to cells, they recruit the target protein to the E3 ligase, hijacking the native degradation pathway to remove the disease target. This protein silencing approach delivers phenotypes that have been called the chemical equivalent to CRISPR – yet with small-molecule control.

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. 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.