A small molecule VHL molecular glue degrader for cysteine dioxygenase 1

Tutter, A.; Buckley, D.; Golosov, A. A.; Ma, X.; Shu, W.; Mckay, D. J.; Darsigny, V.; Dovala, D.; Beckwith, R.; Solomon, J.; Rao, P.; Xu, L.; Fazal, A.; Lingel, A.; Wartchow, C.; Cobb, J. S.; Hachey, A.; Tullai, J.; Michaud, G. A.

doi:10.1101/2024.01.25.576086

bioRxiv · 10.1101/2024.01.25.576086

A small molecule VHL molecular glue degrader for cysteine dioxygenase 1

Tutter, A.·Buckley, D.·Golosov, A. A.·Ma, X.·Shu, W.·Mckay, D. J.·Darsigny, V.·Dovala, D.·Beckwith, R.·Solomon, J.·Rao, P.·Xu, L.·Fazal, A.·Lingel, A.·Wartchow, C.·Cobb, J. S.·Hachey, A.·Tullai, J.·Michaud, G. A.

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Abstract

The Von Hippel-Lindau Tumor Suppressor gene product (pVHL) is an E3 ligase substrate receptor that binds proline-hydroxylated HIF1-, leading to its ubiquitin-dependent degradation. By using protein arrays, we identified a small molecule that binds the HIF1- 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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Tutter, A., Buckley, D., Golosov, A. A., Ma, X., Shu, W., Mckay, D. J., Darsigny, V., Dovala, D., Beckwith, R., Solomon, J., Rao, P., Xu, L., Fazal, A., Lingel, A., Wartchow, C., Cobb, J. S., Hachey, A., Tullai, J., Michaud, G. A.. 2024-01-25. A small molecule VHL molecular glue degrader for cysteine dioxygenase 1. https://doi.org/10.1101/2024.01.25.576086

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