Most targeted protein degraders make use of what is called the ubiquitin-proteasome system, which can be thought of as the recycling system of the cell. However, as will be discussed here, a second protein-degrading pathway is now being explored that involves endocytosis, the process by which substances are brought into the cell. A wide variety of questions about targeted protein degraders is now arising. To begin with, it is not clear what advantage this modality may have over traditional inhibitors that are already on the market. Furthermore, it is uncertain how this emerging class of drugs will perform in upcoming clinical trials. Will they prove to be safe and effective? To get a better understanding of these issues, GEN interviewed experts from five companies to get their views about this exciting new field. The two flavors of targeted protein degradation Most of the companies we interviewed were developing two main types of targeted protein degraders: proteolysis-targeting chimeras (PROTACs) and molecular glues. Both classes make use of the ubiquitin-proteasome system. The purpose of this system is to eliminate misfolded, damaged, and overabundant proteins with a cascade of distinct steps that ultimately involves an enzyme called the E3 ubiquitin ligase. This enzyme promotes the transfer of ubiquitin onto a lysine of the substrate protein. Multiple ubiquitination events signal the death knell for the faulty protein, which is then degraded by the proteasome, the so-called trash can of the cell.
