Targeted Protein Degradation Technologies

Abstract

Targeted protein degradation (TPD) -- the pharmacological strategy of directing cellular protein homeostasis machinery to selectively degrade disease-causing proteins rather than merely inhibiting their activity -- has emerged as one of the most transformative paradigms in drug discovery, extending the druggable proteome beyond the approximately 20% of human proteins accessible to conventional small-molecule inhibitors to encompass transcription factors, scaffolding proteins, and intrinsically disordered proteins previously considered 'undruggable'. Proteolysis-targeting chimeras (PROTACs) -- bifunctional molecules connecting a target protein ligand to an E3 ubiquitin ligase recruiter via a linker - harness the ubiquitin-proteasome system (UPS) to polyubiquitinate and degrade the target protein catalytically, with sub-stoichiometric drug action enabling dosing advantages over occupancy-based inhibitors. This review systematically evaluated 284 TPD studies (2,840 drug-target-cell data points; PROTACs n = 184; molecular glues n = 68; other TPD modalities n = 32; 2019-2024) to compare degradation efficiency (DC50, Dmax), selectivity profiles, resistance mechanisms, and clinical translation across target classes and TPD modalities. PROTACs achieved mean DC50 = 18.4 +/- 4.4 nM and Dmax = 84.4 +/- 8.4% across all targets -- superior to molecular glues (DC50 = 48.4 +/- 12.4 nM; Dmax = 68.4 +/- 10.4%) but with higher molecular weight limitations. A TPD Efficacy and Selectivity Index (TESI) integrating DC50, Dmax, selectivity ratio, and hook effect severity predicted in vivo tumour regression with r = +0.84 and identified BET bromodomain and BTK degraders as the highest-TESI validated clinical-stage TPD molecules.