2. Academic Validation
  3. A small-molecule VHL molecular glue degrader for cysteine dioxygenase 1

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

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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