Ligand for E3 Ligase

 A required PROTAC component is a ligand binding to an E3 ubiquitin ligase, which is then joined to another ligand binding to a protein to be degraded via the ubiquitin–proteasome system. The advent of nonpeptidic small-molecule E3 ligase ligands, notably for von Hippel–Lindau (VHL) and cereblon (CRBN), revolutionized the field and ushered in the design of drug-like PROTACs with potent and selective degradation activity.During the past few years, these efforts have resulted in improved small-molecule-based PROTACs recruiting cereblon (CRBN), von Hippel–Lindau (VHL), and inhibitors of apoptosis proteins (IAPs). By leveraging these small-molecule E3 ligase ligands, the field has since extensively demonstrated that PROTACs can induce degradation of a variety of proteins, even at sub-nanomolar concentrations, and has validated their applications not only as biological tools but also as a new chemical modality for treatment of diseases in the clinic.