Development of PolyHis‐Targeting PROTAC Degraders

Targeted protein degradation (TPD) via proteolysis targeting chimeras (PROTACs) enables selective removal of proteins of interest (POIs) by hijacking the ubiquitin-proteasome system (UPS). However, broad application is constrained by the availability of high-quality target ligands, which remain scarce for much of the human proteome, limiting assessment of POIs for UPS-mediated degradation. To address this challenge, we developed polyhistidine-targeting PROTACs (polyHisTACs) by conjugating a nickel-nitrilotriacetic acid (Ni² ⁺-NTA) headgroup to ligands of VHL or CRBN, thereby recruiting these E3 ligase complexes to polyHis-tagged POIs. As expected, polyHisTACs effectively degraded CRISPR-engineered, endogenously polyHis-tagged BRD4 and also induced robust degradation of an exogenously expressed polyHis-tagged RNA-binding protein, PSPC1, a target that is typically considered undruggable. In summary, polyHisTACs overcome key limitations of existing tag-based degrader systems by leveraging a minimal, easily implemented polyHis tag. This platform provides a versatile, reliable way to evaluate UPS-mediated degradability in the absence of target-specific ligands and serves as a practical tool for acute POI depletion in basic research.