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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月6日

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  • Andrew D. Huber,
  • Wenwei Lin,
  • Young-Hwan Jung,
  • Shyaron Poudel,
  • Guangwei Yang,
  • Jing Wu,
  • Annalise G. Carrigan,
  • Vishwajeeth Pagala,
  • Wei Wang,
  • Yingxue Fu,
  • Zuo-Fei Yuan,
  • Stephanie D. Byrum,
  • Ka Yang,
  • Rebecca R. Florke Gee,
  • Elizabeth D. Arnold,
  • Allister J. Loughran,
  • Jingheng Wang,
  • Shondra M. Pruett-Miller,
  • Junmin Peng,
  • Taosheng Chen

摘要

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.