Target protein recruited for degradation (Protein of Interest) (POI)

The term "Target protein recruited for degradation" refers to a Protein of Interest (POI) that is selectively targeted for elimination by the cell's internal disposal systems, primarily the ubiquitin-proteasome system (UPS) (Sun et al., 2019). This process is typically mediated by Targeted Protein Degradation (TPD) molecules, such as Proteolysis Targeting Chimeras (PROTACs) or molecular glues, which act as bridges between the POI and an E3 ubiquitin ligase (Bekes et al., 2022). Once recruited, the POI undergoes polyubiquitination, signaling the 26S proteasome to degrade the protein into small peptides (Bondeson et al., 2015). This therapeutic strategy is revolutionary because it allows for the targeting of proteins that lack traditional small-molecule binding pockets, often referred to as "undruggable" (Mullard, 2019). By completely removing the protein rather than just inhibiting its activity, TPD can achieve more potent and prolonged biological effects and potentially overcome resistance mechanisms seen with traditional inhibitors (Cromm & Crews, 2017). Common disease areas for this approach include oncology, where proteins like the androgen receptor or BRD4 are frequently targeted (Wang et al., 2020).

Other names

Protein of InterestPOINeosubstrateDegradation targetTargeted protein

Targeted protein degradation (TPD) involving the recruitment of an E3 ubiquitin ligase to a protein of interest, leading to polyubiquitination and subsequent degradation by the 26S proteasome, or via lysosomal/autophagic pathways.