Proteolysis Targeting Chimeras (PROTACs): Mechanisms, Design Strategies, and Therapeutic Applications

Proteolysis-Targeting Chimeras (PROTACs) have emerged as a transformative therapeutic modality capable of inducing selective, catalytic degradation of disease-relevant proteins. These heterobifunctional molecules consist of a ligand for the protein of interest (POI), an E3 ligase recruiter, and a chemical linker that together facilitate formation of a productive ternary complex. By hijacking the Ubiquitin–Proteasome System (UPS), PROTACs promote K48-linked polyubiquitination of the POI, leading to its subsequent degradation by the 26S proteasome. Unlike traditional occupancy-based inhibitors, PROTACs operate through an event-driven mechanism, enabling a single degrader molecule to eliminate multiple POI molecules and achieve potent activity at sub-stoichiometric concentrations. This technology has broadened the druggable proteome, allowing targeted removal of proteins previously considered inaccessible including transcription factors (e.g., MYC, STAT3) and mutant or overexpressed proteins implicated in drug resistance (e.g., BTK C481S, AR-V7). Several PROTACs have progressed into clinical development, most notably ARV-471, the first degrader to undergo New Drug Application (NDA) submission to the U.S. FDA. However, challenges remain, including suboptimal physicochemical properties that often violate the Rule-of-Five, concentration-dependent hook effects, and dependence on a limited set of E3 ligases such as CRBN and VHL. Emerging strategies spanning AI/ML-driven design, expansion of the E3 ligase toolbox, and integration with next-generation modalities such as Nano-PROTACs, antibody–oligonucleotide conjugates (AOCs), and lysosome-directed degradation platforms (e.g., LYTACs) are poised to further advance this rapidly evolving field. This review summarizes the mechanistic basis, design principles, therapeutic potential, and future directions of PROTAC technology, highlighting its growing promise in precision medicine.