Linker attachment points: "finishing touch" in PROTAC design

Proteolysis-targeting chimera (PROTAC) technology is an innovative therapeutic strategy that induces ubiquitination and subsequent proteasomal degradation of target proteins, gaining widespread attention owing to its prominent therapeutic advantages. Current PROTAC design heavily relies on empirical iteration, and their high molecular weight causes poor solubility, permeability and oral bioavailability, which makes linker optimization a critical developmental procedure. Most existing reviews mainly discuss linker length and chemical skeletons, yet rarely conduct a systematic and comprehensive discussion on linker attachment points-the core structural element that determines ternary complex assembly, degradation efficacy and target selectivity. Distinct from previous reviews, this work specially focuses on linker attachment points of both POI ligands and mainstream E3 ligase ligands including CRBN, VHL and IAP. We elaborate how the location and chemical composition of anchoring sites modulate PROTAC degradation performance and pharmacokinetic characteristics, and summarize systematic structure-based rational design rules. This review fills the research gap of specialized summaries on linker attachment engineering and provides practical theoretical guidance for the development of orally bioavailable clinical degraders.