Targeted protein degradation: mechanistic diversity, therapeutic expansion, and clinical translation.
Targeted protein degradation (TPD) has transitioned from a paradigm-shifting concept to a clinically validated strategy, with multiple degraders achieving proof-of-concept in oncology and a rapidly expanding toolbox. By co-opting the ubiquitin-proteasome system to eliminate pathogenic proteins in an event-driven manner, TPD addresses targets long deemed undruggable. To capture this momentum, we present a comprehensive overview of the field. We dissect the mechanisms of heterobifunctional PROTACs and their clinical translation, covering late-stage programs targeting canonical oncogenic drivers (AR, ER, BTK) and emerging first-in-human studies against historically challenging targets such as STAT3 to illustrate both clinical validation and mechanistic expansion. Beyond classical PROTACs, we systematically summarize the expanding TPD toolbox: lysosome-targeting chimeras for degrading extracellular and membrane proteins, autophagy-based degraders for clearing aggregates and damaged organelles, antibody- and nucleic acid-derived PROTAC formats for tissue-specific delivery and transcription factor targeting, deubiquitinase-targeting chimeras for protein stabilization, and proximity-based post-translational modification editing, collectively demonstrating the broad reach of proximity-inducing pharmacology. By integrating molecular mechanisms with therapeutic applications, this review illustrates how TPD is reshaping the druggable proteome. We outline key challenges including novel E3 ligase ligand discovery, tissue selectivity, and acquired resistance, and discuss how covalent fragment screening, artificial intelligence, and expanded E3 ligase repertoires will advance next-generation degraders to fulfill the promise of event-driven pharmacology. This review provides a roadmap for translating TPD into transformative therapies.