Expanding the E3 Ligase Landscape: From Small Molecule to Biological Targeted Protein Degradation

Targeted protein degradation (TPD), particularly proteolysis-targeting chimeras (PROTACs), has emerged as a powerful strategy for eliminating disease-associated proteins through the ubiquitin-proteasome system. However, current PROTACs rely heavily on a limited number of E3 ligases, mainly CRBN and VHL, due to the scarcity of suitable ligands. This review summarizes the development of classical small-molecule E3 ligase ligands and highlights emerging biological recruitment strategies involving antibodies, nanobodies, aptamers, peptides, and engineered proteins. These approaches expand the accessible E3 ligase landscape, broaden the range of targetable proteins, and provide greater programmability and selectivity. Recent advances in delivery systems, modular activation, and artificial intelligence-assisted design are also discussed. Finally, keytranslational challenges, including intracellular delivery, immunogenicity, pharmacokinetics, manufacturing scalability, and off-target effects, are considered. Together, these advances provide a broader framework for developing more precise and versatile next-generation targeted protein degradation platforms.