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Fulvestrant is considered an important source of inspiration for hydrophobic tagging-mediated protein degradation strategies. Studies have shown that, upon binding to the estrogen receptor, fulvestrant induces conformational changes in the receptor ligand-binding domain, thereby exposing previously buried hydrophobic regions on the protein surface; this increases the surface hydrophobicity of the receptor and reduces its stability, ultimately promoting receptor degradation.

In 2011, Neklesa et al. proposed a hydrophobic tagging (HyT)-mediated strategy for targeted protein degradation. The core concept of this strategy is to introduce an artificial hydrophobic moiety onto the surface of a target protein via a small molecule, thereby mimicking the aberrant hydrophobic exposure associated with partial protein denaturation; this induces recognition of the target protein by the cellular protein quality control system and promotes its degradation via the proteasome pathway. To test this hypothesis, the researchers used a HaloTag fusion protein system to design and synthesize a series of bifunctional small molecules composed of a HaloTag-binding moiety and a hydrophobic moiety. Among these, HyT13, which contains an adamantane hydrophobic tag, effectively induced the degradation of HaloTag fusion proteins, and this degradation was blocked by proteasome inhibitors. This study provided the first experimental validation of the feasibility of achieving targeted protein degradation by artificially increasing protein surface hydrophobicity, thereby laying the foundation for the development of hydrophobic tagging technology.

Although early hydrophobic tagging technology successfully achieved targeted degradation of HaloTag fusion proteins, its application relied on fusion expression of the target protein with HaloTag, which limited its ability to directly modulate endogenous proteins. To overcome this limitation, in 2014, Xie et al. extended the adamantane-based hydrophobic tagging strategy to endogenous proteins and developed TX2-121-1, a bifunctional small-molecule degrader targeting human epidermal growth factor receptor 3 (HER3). This study demonstrated that the hydrophobic tagging strategy can directly degrade endogenous proteins via target-specific ligands without relying on the HaloTag fusion system, representing an important step in the transition of HyT technology from tool compounds to small-molecule drugs.