Beyond Inhibition: Proteolysis Targeting Chimeras and the Rise of Targeted Protein Degradation

Abstract

For decades, small-molecule drug discovery has been organized around a single operating principle: a ligand binds a target protein and occupies its active site for long enough to block function. Proteolysis-targeting chimeras (PROTACs) and related targeted protein degradation (TPD) technologies represent a fundamental departure from this occupancy-driven paradigm, instead hijacking the cell's own ubiquitin-proteasome system to mark disease-causing proteins for destruction. Because degraders act catalytically and need only engage a target transiently to trigger its removal, they can address proteins long considered undruggable, including transcription factors, scaffolding proteins, and mutant oncoproteins lacking conventional binding pockets. This review traces the molecular architecture and mechanism of PROTAC-mediated degradation, surveys the expanding clinical pipeline spanning oncology, autoimmune disease, and neurodegeneration, and examines complementary modalities such as molecular glues. We further discuss the principal engineering challenges that continue to shape the field, including the hook effect, limited oral bioavailability associated with high molecular weight, and the restricted repertoire of validated E3 ligases currently exploited for degrader design. We conclude by considering how TPD is likely to mature from a novel modality into a mainstream pillar of medicinal chemistry over the coming decade.