PROTACs

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules capable of inducing Targeted Protein Degradation (TPD) via the recruitment of the ubiquitin–proteasome system (UPS).

The efficacy of degraders derives from the simultaneous engagement of the E3 ligase and the POI. This results in the formation of a stable ternary complex mediating the polyubiquitination of the POI, which is subsequently degraded by the 26S proteasome.

Unlike traditional small-molecule inhibitors, PROTACs operate through an event-driven mode of action. This allows them to target the "undruggable" proteome—including scaffold proteins and transcription factors—without requiring a deep binding pocket.

Among the most remarkable advantages of degraders are their sub-stoichiometric catalytic activity (protein knockdown) and their potential to overcome acquired resistance in cancer treatments, marking a paradigm shift in the drug discovery landscape.

Publications