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<p>The von Hippel–Lindau tumor suppressor gene product (pVHL) is an E3 ligase substrate receptor that binds proline-hydroxylated hypoxia-inducible factor HIF1α, leading to its ubiquitin-dependent degradation. By using protein arrays, we identified a small molecule that binds the HIF1α-binding pocket on pVHL and functions as a molecular glue degrader of the neosubstrate cysteine dioxygenase (CDO1) by recruiting it into the VHL–Cullin–RING E3 ligase complex and leading to its selective degradation. The CDO1-binding region involved in VHL recruitment was characterized through a combination of mutagenesis and protein–protein docking coupled with molecular-dynamics-based solvation analysis. The X-ray structure of the ternary complexes of VHL, CDO1 and degrader molecules confirms the binding region prediction and provides atomic insights into key molecular glue interactions.</p><p></p>

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A small-molecule VHL molecular glue degrader for cysteine dioxygenase 1

  • 期刊论文

  • 发表日期：

    2025年6月24日

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  • Antonin Tutter,
  • Dennis Buckley,
  • Andrei A. Golosov,
  • Xiaolei Ma,
  • Wei Shu,
  • Daniel J. J. McKay,
  • Veronique Darsigny,
  • Dustin Dovala,
  • Rohan Beckwith,
  • Jonathan Solomon,
  • Pasupuleti Rao,
  • Lei Xu,
  • Aleem Fazal,
  • Andreas Lingel,
  • Charles Wartchow,
  • Jennifer S. Cobb,
  • Amanda Hachey,
  • Jennifer Tullai,
  • Gregory A. Michaud

摘要

The von Hippel–Lindau tumor suppressor gene product (pVHL) is an E3 ligase substrate receptor that binds proline-hydroxylated hypoxia-inducible factor HIF1α, leading to its ubiquitin-dependent degradation. By using protein arrays, we identified a small molecule that binds the HIF1α-binding pocket on pVHL and functions as a molecular glue degrader of the neosubstrate cysteine dioxygenase (CDO1) by recruiting it into the VHL–Cullin–RING E3 ligase complex and leading to its selective degradation. The CDO1-binding region involved in VHL recruitment was characterized through a combination of mutagenesis and protein–protein docking coupled with molecular-dynamics-based solvation analysis. The X-ray structure of the ternary complexes of VHL, CDO1 and degrader molecules confirms the binding region prediction and provides atomic insights into key molecular glue interactions.