Redefining Targeted Therapy Through Protein Degradation Using Proteolysis Targeting Chimeras
Keywords:
PROTACs, Targeted Protein Degradation, Ubiquitin–Proteasome System, E3 Ligase, Catalytic Degraders, Molecular Glue, Drug DiscoveryAbstract
Proteolysis Targeting Chimeras (PROTACs) represent a novel class of heterobifunctional molecules designed to induce selective degradation of disease-associated proteins via the ubiquitin–proteasome system. Each PROTAC molecule consists of two ligands, one that binds the protein of interest and another that recruits an E3 ubiquitin ligase, connected by a flexible linker. Upon forming a ternary complex, PROTACs facilitate polyubiquitination of the target protein, marking it for degradation by the 26S proteasome. Unlike traditional inhibitors, PROTACs eliminate proteins rather than inhibit their activity, allowing them to target shallow or transient binding sites and previously “undruggable” proteins. Their catalytic mechanism enables sustained protein knockdown at substoichiometric concentrations. PROTACs are showing promising therapeutic utility, particularly in oncology, where aberrant or misfolded proteins disrupt cellular homeostasis. This review outlines the mechanistic basis of PROTAC function, highlights emerging clinical applications and discusses current challenges and future directions in advancing this transformative therapeutic strategy.
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