Linkerology in PROTACs: learnings for proximity-inducing therapeutics

Targeted protein degradation has rapidly evolved from a chemical biology concept into a therapeutic modality, with the first proteolysis-targeting chimera (PROTAC) degrader now approved as a medicine. Linkers play a central role in governing ternary complex formation and conferring drug-like properties on bifunctional compounds. However, linker optimisation remains one of the least rationalised steps in degrader design. In this review, we introduce a linkerology framework that integrates a data-driven analysis of PROTAC linker chemotypes with historical context, representative case studies, emerging proximity-based modalities, and clinical-stage trends. We reveal persistent biases in the explored linker space and identify linker features that are preferentially retained in clinical-stage degraders. Together, these insights position linkerology as a central discipline in PROTAC design and provide guidance for the development of next-generation proximity-based therapeutics.