An Update on Clinically Advanced PROTAC Degraders and Their Synthesis

Proteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary therapeutic modality that enables degradation of therapeutically relevant proteins through the protein disposal machinery, the ubiquitin-proteasome system (UPS). Unlike traditional small-molecule inhibitors, PROTACs harness bifunctional molecules to induce targeted protein degradation, offering advantages such as increased specificity, catalytic activity, and the potential to address previously undruggable targets. Since their conception 20 years ago, PROTACs have made significant strides in target protein degradation (TPD), and today, PROTACs are on the verge of their first clinical approval. This review presents a detailed overview of PROTAC targets, clinical development progress, and the design and detailed synthesis of degrader molecules that have advanced to clinical trials.