Protein degradation induced by PROTAC molecules as emerging drug discovery strategy
The traditional concept of drug discovery is based on the occupancy-driven pharmacology model. It implies the development of inhibitors occupying binding sites that directly affect protein functions. Therefore, proteins that do not have such binding sites are generally considered as pharmacologically intractable. Furthermore, drugs that act in this way must be administered in dosage regimens that often result in high systemic drug exposures in order to maintain sufficient protein inhibition. Thus, there is a risk of off-target binding and side effects onset. The landscape of drug discovery has been markedly changed since PROTAC (PROteolysis TArgeting Chimera) molecules emerged twenty years ago as a part of event-driven pharmacology model. These are bifunctional molecules that harness the ubiquitin-proteasome system, and are composed of a ligand that binds protein of interest (POI), a ligand that recruits E3 ubiquitin ligase and a linker that connects these two parts. Pharmacologically, PROTAC s bring POI and E3 ubiquitin ligase into the close proximity, which triggers the formation of a functional ternary complex POI-PROTAC -E3 ubiquitin ligase. This event drives POI polyubiquitination and subsequent degradation by the 26S proteasome. The development and exceptional properties of PROTAC molecules that brought them to clinical studies will be discussed in this paper.