The Expanding E3 Ligase-Ligand Landscape for PROTAC Technology

作者：Zhenzhen Li, Xiaoli Huang, Xuchi Zhao, Yunxiu Zhang, Ping Li · 发表于：Targets · 年份：2025 · DOI：10.3390/targets3040030 · 被引用次数：4 · 研究领域：Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways、Multiple Myeloma Research and Treatments

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.