Mighty mini-PROTACs: an emerging class of degraders

Proteolysis-targeting chimera (PROTAC) is an emerging therapeutic strategy that rewires the ubiquitin-proteasome system to destroy pathogenic proteins. Despite tremendous progress, PROTACs still face significant challenges in their development and clinical application. The historically first and simplest degradation signal is a single amino acid, leading to the N-end rule proteolytic pathway, but its PROTAC adaptation has been under-explored. Here, we examine the feasibility of the N-end rule pathway in addressing some major issues in the field and introduce the resulting mini-PROTACs bearing small, diverse, and interchangeable degrons. Such an approach potentially helps overcome resistance issues associated with existing ubiquitin ligases as well as helps enhance drug-like properties. Finally, we discuss the advantages and limitations of mini-PROTACs compared to other classical PROTACs, which will facilitate their clinical applications.