Targeted protein degradation (TPD) has emerged as a chemical strategy to modulate proteostasis, offering important advantages over traditional small molecules. By inducing proximity between a protein of interest (POI) and the cellular degradation machinery, protein degraders enable selective and dynamic degradation of the POI. Unlike classical small molecules (i.e. inhibitors), the event-driven mode of action of chemical degraders offers new therapeutic opportunities for previously intractable diseases. Molecular glues (MGs) and proteolysis-targeting chimeras (PROTACs) can target proteins previously considered undruggable, including those lacking catalytic activity or deep binding pockets, such as transcription factors and scaffold proteins. TPD has gained substantial attention in drug discovery, with several candidates advancing in clinical trials, validating chemically induced proximity as therapeutic strategy. However, in plants, the development of synthetic degraders remains largely unexplored. Here, we review the molecular basis of TPD, with emphasis on MGs and PROTACs. We discuss critical aspects of PROTAC design, including E3 ligase suitability, target selection, and linker optimization. We also summarize engineered tag-based systems and emerging non-proteasomal modalities. Finally, we provide a critical evaluation of the opportunities and limitations of protein degraders and provide a theoretical and practical framework to facilitate the expansion of TPD in plant biology and agriculture.
Donderis-Fagoaga et al. (Tue,) studied this question.