Proteolysis-targeting chimeras (PROTACs) are a transformative therapeutic modality that co-opts the ubiquitin-proteasome system for selective protein degradation. To date, the development of PROTACs has been overwhelmingly dominated by the recruitment of four canonical E3 ligases: CRBN, VHL, MDM2, and IAP. This limited repertoire represents a critical bottleneck, restricting the scope of degradable proteins and potential therapeutic applications. Addressing this challenge, recent years have witnessed a surge in the successful recruitment of novel E3 ligases. This review provides a dedicated and comprehensive summary of this progress, focusing exclusively on the emerging E3 ligases and their cognate ligands reported for PROTAC technology outside of the well-established quartet. We detail their discovery and strategic application, highlighting how this rapidly expanding toolbox promises to overcome existing limitations and unlock the full potential of targeted protein degradation.
Li et al. (2025) studied this question.