Tissue-enriched degrader receptor

Tissue-enriched degrader receptors are a specialized class of cell-surface or transmembrane proteins, such as E3 ubiquitin ligases or internalizing receptors, that exhibit high or exclusive expression in specific tissues or disease-associated cells compared to healthy tissues (EpiBiologics, 2024). These receptors serve as the "effector" component in targeted protein degradation (TPD) strategies, such as the EpiTAC platform, to mediate the selective destruction of extracellular or membrane-bound proteins of interest (POI) (AACR, 2025). By employing bispecific molecules—such as antibodies or small molecules—that simultaneously engage the POI and a tissue-enriched degrader receptor, the POI is selectively recruited to the cell's internal degradation machinery (Trends in Cell Biology, 2024). Depending on the receptor type, this recruitment leads to either ubiquitination and proteasomal degradation (via transmembrane E3 ligases like RNF43 or ZNRF3) or internalization and lysosomal degradation (via receptors like ASGPR or CD71) (Frontiers in Pharmacology, 2024). This approach significantly enhances the therapeutic index by restricting degradation activity to the target tissue, thereby avoiding the systemic toxicities often associated with ubiquitous E3 ligases like Cereblon (CRBN) or Von Hippel-Lindau (VHL) (Drug Hunter, 2025). This technology is particularly promising for targeting previously "undruggable" extracellular proteins in oncology, immunology, and neurodegeneration.

Other names

Degrader receptorTissue-specific E3 ligaseInternalizing receptorEpiAtlas receptorEffector protein (in TPD)

Recruitment of a target protein of interest (POI) to a tissue-specific effector (either a transmembrane E3 ubiquitin ligase or an internalizing receptor) via a bispecific molecule to induce proximity-driven degradation through the proteasomal or lysosomal pathways.