Recent Advances in the Development of Pro-PROTAC for Selective Protein Degradation

PROTACs are trimeric small molecules consisting of a specific modulator of the target protein connected to a ligase-recruiting ligand via a suitably flexible linker. Ligase-recruiting ligands deliver ubiquitin ligases like E3 ligase to the Protein of Interest (POI). The vicinity of the POI-PROTAC-E3 ternary complex enables the E3 ligase to ubiquitinate the surface lysine residues of the POI. The Ubiquitin-Proteasome System (UPS) then degrades the POI. However, despite the considerable advances in the design of PROTACs targeting several types of enzymes and receptors, this strategy is still facing the challenges of precision target delivery and duration of action. In this review, we highlight the recent approaches for the development of PROTAC prodrugs or pro-PROTAC to control the delivery of PROTACs and achieve the required on-target exposure. This strategy may facilitate the application of the PROTAC technology and expand its clinical benefits.