Small-Molecule Hydrophobic Tagging: A Promising Strategy of Druglike Technology for Targeted Protein Degradation Miniperspective

Targetedprotein degradation (TPD) technologies havecatalyzeda paradigm shift in therapeutic strategies and offer innovative avenuesfor drug design. Hydrophobic tags (HyTs) are bifunctional TPD moleculesconsisting of a & DPRIME;lipophilic small-molecule tags & DPRIME; groupand a small-molecule ligand for the target protein. Despite the vastpotential of HyTs, they have received relatively limited attentionas a promising frontier. Leveraging their lower molecular weight andreduced numbers of hydrogen bond donors/acceptors (HBDs/HBAs) in comparisonwith proteolysis-targeting chimeras (PROTACs), HyTs present a compellingapproach for enhancing druglike properties. In this Perspective, weexplore the diverse range of HyT structures and their correspondingdegradation mechanisms, thereby illuminating their broad applicabilityin targeting a diverse array of proteins, including previously elusivetargets. Moreover, we scrutinize the challenges and opportunitiesentailed in developing this technology as a viable and fruitful strategyfor drug discovery.