Co-crystal structures for VHL-based degraders 44 and 45 were solved with structures determined in a crystal form with four molecules in the asymmetric unit. The VHL-binding moiety was always disordered in these structures, but the linker was visible in most of the chains. When the linker was visible, it always packed against the hydrophobic surface patch between Phe79 and Leu148 (Figure ), although this may be influenced by crystal packing. The increased affinity compared with the parent scaffold may be due to such a hydrophobic interaction of the linker with a hydrophobic surface patch. The E3 ligase ligand is clearly solvent exposed (as opposed to 35) and this may also explain its ability to ubiquitinate BRD4. The aliphatic linker packed against the surface patch between Phe79 and Leu148, whereas the VHL moiety was largely unresolved in the crystal structure, indicating high flexibility. For clarity, only the protein chain for the complex with 44 is shown.