Next-Generation Proteolysis-Targeting Chimeras in Precision Oncology: Multifunctional Designs, Emerging Modalities, and Translational Prospects in Targeted Protein Degradation.

Proteolysis-targeting chimeras (PROTACs)-mediated protein degradation has been recently developed as a game-changing approach in oncology drug development. It represents a paradigm shift from traditional enzyme inhibition to selective protein degradation. PROTACs are different from regular small-molecule inhibitors because they are heterobifunctional compounds that use the ubiquitin-proteasome system to breakdown disease-causing oncogenic proteins. This review discusses the next generation of PROTAC platforms that innovate beyond traditional designs, such as dual-targeting PROTACS that present a novel mode of action, transcription factor-targeting PROTACs (TF-PROTACs), phosphorylation-dependent PROTACs (PhosphoTACs), and phosphorylation binding chimeras (PhosTACs). In kinase degradation, PROTACs have shown promise in addressing resistance mechanisms and carcinogenic drivers. Despite these advancements, issues with clinical pharmacokinetics, E3 ligase tissue selectivity, and subcellular localization persist. Additionally, the development of bio-responsive and spatially controlled PROTAC systems, such as photocaged and folate-caged PROTACs, was fully discussed, which achieves maximal precision in tumor selectivity. Furthermore, ARV-110 and ARV-471, as two representative PROTACs, have entered clinical trials, suggesting their potentially broader application. Accordingly, this review provides a critical overview of the design rationales, molecular mechanisms of action, therapeutic utilities, and synthetic issues associated with these innovative modalities, focusing on on their translational implication and pharmacokinetic limitations, as well as potential future clinical applications.