PROTAC ® Protein Degraders: Bridging the Divide from Chemical Biology Tools to Clinical Candidates

The ubiquitin–proteasome system (UPS) comprises E1, E2, and E3 enzymes to prime and attach ubiquitin moieties to target substrates. Substrates can be modified with a single ubiquitin moiety, or with many, arranged as single modifications on multiple sites or one chain on a single substrate residue. Different linkage types increase complexity further, and the resultant ubiquitin code regulates not just proteasomal degradation of substrates but a range of other activities. Based on their E2 binding domains, the E3 enzymes that transfer ubiquitin to the substrate fall into three broad categories, RING, HECT, and RBR E3s, whose structures and mechanisms are outlined below. An overview of their functions is also provided, as well as discussion on the knowledge gaps within the ubiquitin field and how the development of PROTACs and molecular glues can benefit both from the current understanding and further research in this area to drive advances in chemical targeting.