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. 2025 Jun 24.
doi: 10.1038/s41589-025-01936-x. Online ahead of print.

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

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

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

Antonin Tutter et al. Nat Chem Biol. .

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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Conflict of interest statement

Competing interests: All authors are or were employees of Novartis Biomedical Research and may have held stock in Novartis when the research for the manuscript was performed.

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