Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design

Proteolysis-targeting chimeras (PROTACs) as an emerging drug discovery modality has been extensively con-cerned in recent years. Over 20 years development, accumulated studies have demonstrated that PROTACs show unique advantages over traditional therapy in operable target scope, efficacy, and overcoming drug resistance. However, only limited E3 ligases, the essential elements of PROTACs, have been harnessed for PROTACs design. The optimization of novel ligands for well-established E3 ligases and the employment of additional E3 ligases remain urgent challenges for investigators. Here, we systematically summarize the current status of E3 ligases and corresponding ligands for PROTACs design with a focus on their discovery history, design principles, application benefits, and potential defects. Meanwhile, the prospects and future directions for this field are briefly discussed.

Automated summary

Proteolysis-targeting chimeras (PROTACs) have gained significant attention as an emerging modality in drug discovery. After over 20 years of development, accumulated studies have shown that PROTACs offer unique advantages over traditional therapy in terms of target scope, efficacy, and overcoming drug resistance. However, the limited availability of E3 ligases, essential components of PROTACs, poses a challenge for their design. This review provides a systematic summary of the current status of E3 ligases and corresponding ligands for PROTACs design, including their discovery history, design principles, application benefits, and potential limitations. The prospects and future directions in this field are also briefly discussed.