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.
Despite the many advantages of PROTACs outlined in this review, not all the targets are suitable for PROTAC mediated degradation. Therefore, validation and filtering procedures could enable efficient PROTAC drug candidate prioritization and sorting. Together with other novel approaches that induce degradation based on proximity, like LYTAC, AUTAC, ATTEC and RIBOTAC, the target degradation community will open up new possibilities for drug discovery and provide tangible therapeutic benefits.
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