Journey of Von Hippel-Lindau (VHL) E3 ligase in PROTACs design: From VHL ligands to VHL-based degraders

The scientific community has shown considerable interest in proteolysis-targeting chimeras (PROTACs) in the last decade, indicating their remarkable potential as a means of achieving targeted protein degradation (TPD). Not only are PROTACs seen as valuable tools in molecular biology but their emergence as a modality for drug discovery has also garnered significant attention. PROTACs bind to E3 ligases and target proteins through respective ligands connected via a linker to induce proteasome-mediated protein degradation. The discovery of small molecule ligands for E3 ligases has led to the prevalent use of various E3 ligases in PROTAC design. Furthermore, the incorporation of different types of linkers has proven beneficial in enhancing the efficacy of PROTACs. By far more than 3300 PROTACs have been reported in the literature. Notably, Von Hippel-Lindau (VHL)-based PROTACs have surfaced as a propitious strategy for targeting proteins, even encompassing those that were previously considered non-druggable. VHL is extensively utilized as an E3 ligase in the advancement of PROTACs owing to its widespread expression in various tissues and well-documented binders. Here, we review the discovery of VHL ligands, the types of linkers employed to develop VHL-based PROTACs, and their subsequent modulation to design advanced non-conventional degraders to target various disease-causing proteins. Furthermore, we provide an overview of other E3 ligases recruited in the field of PROTAC technology.