Fulfilling multiple roles in PROTAC design: The emerging potential of oligonucleotides

The field of targeted protein degradation (TPD) has emerged as a novel therapeutic approach based on event-driven pharmacology, rather than on continuous occupancy or inhibition of a target. Proteolysis-targeting chimeras (PROTACs) are one of the main TPD modalities, enabling a protein of interest (POI) to be brought into proximity with a ubiquitin ligase, which facilitates ubiquitination of the target protein, leading to its degradation. The design of PROTACs involves the development of heterobifunctional compounds composed of three parts: a POI ligand, a linker, and an E3 ligase ligand. To date, PROTAC technology has been applied to degrade a wide range of targets, with particular interest in previously "undruggable" targets, such as transcription factors. In this context, oligonucleotides have emerged as potential POI binders for transcription factors, since these targets naturally bind to DNA to modulate gene expression. This has led to the development of oligonucleotide-based degraders. Moreover, the role of oligonucleotides has expanded beyond their use as POI ligands. Several strategies have been explored to overcome inherent challenges such as poor stability and limited drug delivery. Currently, novel approaches also demonstrate the potential of nucleotides to function as linkers, where they can exert control over the spatial orientation between the POI ligand and the E3 ligase ligand, thereby optimizing ternary complex formation. In addition, nucleotides can also serve as E3 ligase ligands. Oligonucleotides represent a promising approach in PROTAC design, capable of fulfilling multiple functional roles.