From discovery to clinic: Medicinal chemistry strategies for PROTAC linker optimization

Proteolysis-targeting chimeras (PROTACs) hold great promise for degrading undruggable proteins, yet their clinical advancement is often limited by poor pharmacokinetics and low oral bioavailability. These challenges are intrinsically related to the physicochemical characteristics of the linkers. This review systematically examines medicinal chemistry strategies for linker optimization, with a particular focus on structure-activity relationships (SAR) derived from clinical-stage PROTACs. We dissect representative case studies of typical candidates to illustrate how rational linker design, encompassing alkyl chain rigidification, heteroatom incorporation, and the introduction of conformational constraints, effectively enhances metabolic stability, cellular permeability, and overall degradation efficiency. Despite progress in linker optimization, key challenges persist. We aim to underscore cases of clinical compound, providing new prospects for future drug discovery through innovation in medicinal chemistry.