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

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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Publication Details

Journal
Nature Communications
Published
2025-11-06
DOI
https://doi.org/10.1038/s41467-025-64773-5
Citations
1
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
0.81

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article

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

Andrew D. Huber, Taosheng Chen, Junmin Peng, Jingheng Wang et al.
1 citations
Nature Communications
Protein Degradation and Inhibitors
0.81
article

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

Andrew D. Huber, Taosheng Chen, Junmin Peng, Jingheng Wang, Yingxue Fu, Shondra M. Pruett‐Miller, Shyaron Poudel, Vishwajeeth Pagala, Stephanie D. Byrum, Elizabeth D. Arnold, Allister J. Loughran, Ka Yang, Zuo‐Fei Yuan, Wenwei Lin, Allison Carrigan, Rebecca R. Florke Gee, Wei Wang, Guangwei Yang, Jing Wu, Kwan‐Young Jung
article en
1 citations

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.

Nature CommunicationsVol. 16(1)
St. Jude Children's Research Hospital (US)
University of Pittsburgh, American Lebanese Syrian Associated Charities, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences
Openalex Percentile: Top 22%
Protein Degradation and Inhibitors
0.81
DOIOpen Access PDFOpenAlex
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