Targeting Cancer Cells via N-degron-based PROTACs

In mammals, protein degradation is mediated selectively by the ubiquitin proteasome system (UPS) and the autophagic-lysosomal system. Over the past decades, N-degron pathways have been shown to be responsible for the selective degradation of proteins that harbor destabilizing N-terminal motifs. Recent studies have employed these pathways in the development of proteolysis targeting chimeras (PROTACs) composed of a degradation module linked to a substrate recognition domain to target proteins encoded by cancer-related genes for proteasomal destruction. Herein we provide an overview of PROTACs in the context of the N-degron concept and address the application of this technique to curb the migration and invasion of cancer cells, with a focus on the far-reaching potential of exploiting N-degron pathways for therapeutic purposes.