PROTACs coupled with oligonucleotides to tackle the undruggable.

Undruggable targets account for roughly 85% of human disease-related targets and represent a category of therapeutic targets that are difficult to tackle with traditional methods, but their considerable clinical importance. These targets are generally defined by planar functional interfaces and the absence of efficient ligand-binding pockets, making them unattainable for conventional pharmaceutical strategies. The advent of oligonucleotide-based proteolysis-targeting chimeras (PROTACs) has instilled renewed optimism in addressing these challenges. These PROTACs facilitate the targeted degradation of undruggable entities, including transcription factors (TFs) and RNA-binding proteins (RBPs), via proteasome-dependent mechanisms, thereby presenting novel therapeutic approaches for diseases linked to these targets. This review offers an in-depth examination of recent progress in the integration of PROTAC technology with oligonucleotides to target traditionally undruggable proteins, emphasizing the design principles and mechanisms of action of these innovative PROTACs.