Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms

The onset of proteolysis targeting chimeras (PROTACs) has reshaped the entire context of targeted cancer therapy by offering a novel approach for the selective degradation of disease-causing proteins, overcoming the limitations of traditional occupancy-driven inhibition. This heterobifunctional technology recruits endogenous E3 ubiquitin ligases to mark proteins of interest (POI) for proteosomal degradation via the ubiquitin-proteasome system (UPS). Unlike conventional inhibitors, PROTACs function catalytically and can target previously “undruggable proteins”, such as transcription factors, scaffold proteins, and non-enzymatic regulators, offering potential to overcome acquired resistance and achieve potent efficacy at sub-stoichiometric doses. The review explores the latest innovations in PROTAC design, including E3 ligase selection, linker chemistry, and ligand optimization, while highlighting promising preclinical and clinical candidates against oncogenic drivers, anti-apoptotic factors (BCL-xL), and nuclear hormone receptors. Furthermore, we critically examine key translational challenges, such as pharmacokinetics, off-target effects, and resistance mechanisms, and discuss viable solutions, including dual E3 ligase engagement, novel modalities like AUTACs/ATTECs, LYTACs, and AI-driven design. As the field rapidly evolves from foundational to clinical application, PROTACs are redefining therapeutic possibilities, offering a robust, flexible, and scalable framework for the future of precision oncology.