Library of Hydrophobic Tag-Based Targeted Protein Degraders (HyT-TPDs)

Hydrophobic Tag-Based Protein Degradation (HyT-PD): HyT-PDs are bifunctional compounds linking a POI ligand to a hydrophobic moiety (e.g., adamantane, fluorene, terpenes) that acts as a hydrophobic tag (HyT).
The cellular protein quality control (PQC) system recognizes the tagged POI as misfolded, triggering degradation through multiple pathways, including UPS, lysosomal autophagy, unfolded protein response (UPR), or ubiquitin-independent proteasome system (UIPS).
This mechanistic diversity is a key advantage, though the specific pathway in each case requires further study.
Compared to PROTACs, HyT-PDs have lower molecular weight, reduced HBD/HBA, lower PSA, and improved cell permeability and PK. Some HyT-PDs can also cross the blood-brain barrier (BBB).
Rational design of HyT-PDs is simpler than PROTACs. While selecting an effective POI ligand remains challenging, existing hydrophobic tags can be readily used, and linker length is less critical.
Development of a HyT-PD Library: Motivated by these advantages, we developed a library of HyT-PDs. Library members were selected using computational methods, including 2D/3D shape and similarity analyses, targeting proteins relevant to oncology, immunology, and inflammation.

All compounds feature a hydrophobic, conformationally constrained moiety (e.g., adamantane, norbornene, norbornane, fluorene, menthol) as the HyT.
This library serves as a valuable resource for researchers developing novel therapeutics to target undruggable proteins and address drug resistance.

References:
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