Trivalent PROTACs speed up protein degradation

Targeted degradation of proteins in the cell has the potential to be useful in treating disease or as a research tool. A class of protein degraders that have attracted significant research interest because of their ability to degrade a variety of proteins is known as proteolysis-targeting chimeras, or PROTACs. These molecules typically consist of two ligands. One ligand binds the targeted protein, and the other binds an enzyme that adds the protein ubiquitin to the target protein as a signal to the cell that the protein is slated for degradation. The PROTAC brings the target protein and the enzyme close enough for the enzyme to do its job. A new study reports PROTACs with three ligands, two that bind sites on the target protein and one that binds the enzyme. The new trivalent PROTACs achieve protein degradation at lower concentrations than conventional bivalent PROTACs ( Nat. Chem. Biol. 2021, DOI: