Protein degradation induced by PROTAC molecules as an emerging drug discovery strategy

Abstract

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 the onset of off target binding and side effects. The landscape of drug discovery has been markedly changed since proteolysis targeting chimera (PROTAC) molecules emerged twenty years ago as a part of the event-driven pharmacology model. These are bifunctional molecules that harness the ubiquitin-proteasome system, and are composed of a ligand that binds the protein of interest (POI), a ligand that recruits E3 ubiquitin ligase (E3UL) and a linker that connects these two parts. Pharmacologically, PROTACs bring POI and E3UL into close proximity, which triggers the formation of a functional ternary complex POI– –PROTAC–E3UL. This event drives polyubiquitination and subsequent POI 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.

Keywords

• bifunctional molecules
• ternary complex
• cooperativity
• polyubiquitination
• undruggable proteome
• clinical candidates