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

  • Nat Chem Biol. 2025 Nov;21(11):1688-1696. doi: 10.1038/s41589-025-01936-x.
Antonin Tutter  1 ,  Dennis Buckley  1 ,  Andrei A Golosov  2 ,  Xiaolei Ma  3 ,  Wei Shu  3 ,  Daniel J J McKay  2 ,  Veronique Darsigny  1 ,  Dustin Dovala  4 ,  Rohan Beckwith  1 ,  Jonathan Solomon  1 ,  Pasupuleti Rao  1 ,  Lei Xu  1 ,  Aleem Fazal  1 ,  Andreas Lingel  5 ,  Charles Wartchow  4 ,  Jennifer S Cobb  1 ,  Amanda Hachey  1 ,  Jennifer Tullai  1 ,  Gregory A Michaud  6
Affiliations
  • 1. Discovery Sciences, Novartis Biomedical Research, Cambridge, MA, USA.
  • 2. Global Discovery Chemistry, Novartis Biomedical Research, Cambridge, MA, USA.
  • 3. Global Discovery Chemistry, Novartis Biomedical Research, Emeryville, CA, USA.
  • 4. Discovery Sciences, Novartis Biomedical Research, Emeryville, CA, USA.
  • 5. Global Discovery Chemistry, Novartis Biomedical Research, Basel, Switzerland.
  • 6. Discovery Sciences, Novartis Biomedical Research, Cambridge, MA, USA. [email protected].
PMID: 40555806 DOI: 10.1038/s41589-025-01936-x
Abstract

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.

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