A small molecule VHL molecular glue degrader for cysteine dioxygenase 1

Abstract The Von Hippel-Lindau Tumor Suppressor gene product (pVHL) is an E3 ligase substrate receptor that binds proline-hydroxylated HIF1-α, leading to its ubiquitin-dependent degradation. By using protein arrays, we identified a small molecule that binds the HIF1-α 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.