E3 Ligase Ligand-Linker Conjugate

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. Enabled by the discoveries of high-quality, crystallographically defined ligands for the E3 ligases VHL and CRBN, PROTACs have had a meteoric resurgence in the limelight, a remarkable development that has culminated in the first PROTAC degraders being demonstrated as safe and efficacious in the clinic.