Clinical Translation of Targeted Protein Degraders

Targeted protein degradation (TPD) is a promising therapeutic approach that uses molecular glue degraders and heterobifunctional proteolysis targeting chimeras (PROTACs) to induce the degradation of proteins-of-interest (POIs), including those previously considered undruggable. These degraders work by hijacking the ubiquitin machinery, leading to the polyubiquitination and proteasomal degradation of target proteins. There has been a significant increase in the number of degraders entering clinical trials, especially for cancer treatment, with most utilizing the CRL4^CRBN E3 ligase. However, the diversity of POIs targeted remains limited. This review discusses the degraders in clinical trials, lessons learned from their development, and emerging human data, providing valuable insights for those in the TPD field.