Hydrophobic tagging: A promising paradigm for targeted protein degradation.

Targeted protein degradation (TPD) has emerged as a groundbreaking therapeutic strategy, overcoming the limitations of traditional occupancy-driven pharmacology. Among TPD strategies, hydrophobic tag (HyT) technology exemplifies this paradigm shift by hijacking cellular protein quality control mechanisms for precise protein elimination. Structurally, HyT molecules integrate a target-specific ligand with a hydrophobic domain that emulates misfolded protein surfaces, facilitating selective recruitment of chaperone systems (e.g., heat shock protein 70, HSP70) and ubiquitin-proteasome system (UPS) activation, circumventing the E3 ligase dependency inherent to proteolysis-targeting chimera (PROTAC) systems. This innovative strategy offers distinct therapeutic benefits, including enhanced tissue-specific accumulation and the capacity to overcome resistance mechanisms. This review highlights the important advances in this rapidly growing field and critical limitations encountered in developing HyT degraders by analyzing the current status and representative examples of HyTs in degrading diverse pathogenic proteins, including oncogenic drivers (e.g., signal transducer and activator of transcription 3, STAT3), neurodegenerative aggregates (tau, α-synuclein), and viral envelope proteins. The critical developments, including the rational design of hydrophobic motifs and possible mechanistic insight into the degradation process of HyTs, have also been discussed.