Having established the suitability of disulfides as DCC motif in stable, isolatable compounds and the vital correlation between induction of ternary complex formation and degrader potency, we set out to characterize the identified novel degraders in depth and selected SH2 as representative for this extended characterization studies. To gain mechanistic insight into the mode of action of disulfide-containing Homo-PROTACs, we performed cotreatments of degrader SH2 along with the proteasome inhibitor MG132, the neddylation inhibitor MLN4924 as well as with the potent VHL inhibitor VH298 (Figure ). VHL protein levels were rescued in all three cases, indicating that VHL degradation is dependent on the proteasomal degradation pathway, on the activity of the CRL VHL ligase and specifically on binding to VHL, respectively, as the expected PROTAC mode of action.