2. Academic Validation
  3. PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors

PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors

  • Nat Commun. 2025 Nov 6;16(1):9805. doi: 10.1038/s41467-025-64773-5.
Andrew D Huber 1,  Wenwei Lin 1,  Young-Hwan Jung 1,  Shyaron Poudel 1,  Guangwei Yang 1,  Jing Wu 1,  Annalise G Carrigan 1,  Vishwajeeth Pagala 2,  Wei Wang 2,  Yingxue Fu 2,  Zuo-Fei Yuan 2,  Stephanie D Byrum 2,  Ka Yang 3,  Rebecca R Florke Gee 1 4,  Elizabeth D Arnold 5 6,  Allister J Loughran 5 6,  Jingheng Wang 1,  Shondra M Pruett-Miller 5 6,  Junmin Peng 3 7,  Taosheng Chen 8
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 2 Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4 Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 5 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 6 Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 7 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 8 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA. [email protected].
PMID: 41198675 DOI: 10.1038/s41467-025-64773-5
Abstract

Proteolysis-targeting chimeras (PROTACs) containing a target protein ligand linked to an E3 ubiquitin Ligase ligand induce target protein degradation through E3 recruitment. Most PROTACs bind a surface cleft of the protein of interest rather than a buried pocket. Using the nuclear receptor PXR, we previously described the inherent difficulties of PROTAC targeting via a deep solvent-inaccessible ligand binding pocket. Here, we discover that the CRBN-dependent MDM2 PROTAC MD-224 is a potent PXR degrader that achieves its activity from binding adjacent to the ligand-binding pocket. Furthermore, because the proximal region is a structural feature common among nuclear receptors, MD-224 also targets additional receptors for proteasomal degradation. Using structure- and activity-guided medicinal chemistry, we ablated MDM2 degradation and generated MD-224 analogs with activities skewed toward different receptors. Thus, we describe (1) PROTAC repurposing as a potential route of degrader discovery and (2) nuclear receptor-targeted degradation through a noncanonical binding site.

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