Based on these criteria, we selected the disulfide exchange reaction as reversible chemistry to build the DCL, because it features mild and protein-benign reversible reaction conditions, easy freezing of the equilibrium by acidification, and provides molecules expected to be sufficiently stable for isolation and testing. As disulfides are formed through dimerization of thiols, the chemical handle on both constituting building blocks is identical in the disulfide exchange reaction. As such both homodimeric (A-A and B-B) and heterodimeric (A-B) products can be formed in this reaction. To allow exploiting not only heterodimeric, but also the homo-dimeric products of the reversible disulfide exchange and maximize the number of on-target PROTACs formed during building block scrambling, we decided to leverage our previously reported VHL-targeting Homo-PROTACs, where the protein VHL serves as both the E3 ligase and the target protein, mediating its own degradation. We envisaged that, in a DCC setting, formation of homo-dimeric scrambling products will lead to symmetric Homo-PROTACs, while hetero-dimeric scrambling will give rise to asymmetric Homo-PROTACs.