PROTACs: past, present and future.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of one ligand that binds to a protein of interest (POI) and another that can recruit an E3 ubiquitin ligase. The chemically-induced proximity between the POI and E3 ligase results in ubiquitination and subsequent degradation of the POI by the ubiquitin-proteasome system (UPS). The event-driven mechanism of action (MOA) of PROTACs offers several advantages compared to traditional occupancy-driven small molecule inhibitors, such as a catalytic nature, reduced dosing and dosing frequency, a more potent and longer-lasting effect, an added layer of selectivity to reduce potential toxicity, efficacy in the face of drug-resistance mechanisms, targeting nonenzymatic functions, and expanded target space. Here, we highlight important milestones and briefly discuss lessons learned about targeted protein degradation (TPD) in recent years and conjecture on the efforts still needed to expand the toolbox for PROTAC discovery to ultimately provide promising therapeutics.