Protein degraders

Recent therapeutic advances have seen ways around so-called ‘undruggable’ proteins. Many of these are multispecific approaches, in which the therapeutic candidate binds to both a target and another biomolecule of interest (e.g. targeted protein degradation with PROTACs). Here, Carolyn Bertozzi and colleagues report lysosome-targeting chimaeras, which they term LYTACs. These are molecules containing a small molecule or antibody connected to a glycopeptide ligand, which can bind a cell surface lysosome shuttling receptor and a protein target. The LYTAC concept is demonstrated by the degradation of a series of therapeutically relevant proteins, including EGFR and PD-L1. This approach expands targeted protein degradation to extracellular and membrane proteins, which comprise 40% of the human proteome.