PROTACs in targeted protein degradation: Advances in development and AI-enhanced drug discovery

Targeted protein degradation (TPD) eliminates disease-relevant proteins by engaging endogenous proteolytic machinery, most prominently the ubiquitin-proteasome system (UPS). Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules composed of a protein of interest (POI) ligand, an E3 ligase recruiter, and a linker. By bringing the POI and E3 ligase into proximity, PROTACs promote POI ubiquitination and subsequent proteasomal degradation, and multiple candidates have progressed into clinical trials. This review summarizes the structural and mechanistic principles that govern PROTAC efficacy, selectivity, and degradation kinetics, and highlights key modality innovations and representative clinical progress with an emphasis on chemical structures, quantitative degradation metrics, and structure-activity relationships. We then examine key translational bottlenecks, including ternary-complex (TC) dependence, the hook effect, limited E3 ligase options, context-dependent selectivity, permeability, and beyond-Rule-of-Five (bRo5) properties, and discuss practical medicinal chemistry strategies to address these challenges. Finally, we describe how computational modeling and AI can be integrated across the design-make-test cycle, and summarize emerging data resources that enable more prospective, data-driven PROTAC discovery.