Our data thus suggests that VHL can 'win the battle' with CRBN when the two ligases are brought together by a PROTAC. Future mechanistic studies are warranted to attempt to elucidate the contributors for this preferential unilateral outcome of our 'double-hijacking' approach. We also cannot exclude that different combinations of conjugation patterns (via different attachment points for example) and linker lengths and structures of CRBN-VHL PROTACs might be able to discriminate different relative orientation of the ternary complex in such a way that the outcome might become reverse, i.e. VHL being preferentially degraded over CRBN -a hypothesis that will be tested in future work. In this regard, it is interesting to note that minor concentration-dependent depletion of pVHL30 was observed at the lower end of the concentration range (5-50 nM) in HeLa (Figure ) as well as in the screen at lower compound concentration (10 nM, Figure ). pVHL30 is the VHL isoform that is preferentially degraded by the homo-PROTAC CM11. No observable PROTAC-induced degradation of pVHL19 was instead observed with any of our compounds, consistent with the cellular outcome observed with CM11. These observations together suggest an enticing possibility that differential ligase degradation might apply at distinct ranges of concentration of CRBN-VHL dimerizers. Differential absolute concentration between the two E3 ligases, and/or differential binding affinities of each end of the bivalent molecule for its respective ligase, are likely to be amongst the contributing factors that could effectively skew the hook effect towards one ligase versus the other one depending on the PROTAC concentration, ultimately imparting differential protein degradation outcomes. Such an effect could be of relevance in a broader context for other E3 ligase pairs. It is noteworthy that a recent study reported MDM2 PROTAC degraders, designed by linking an MDM2 inhibitor via either a thalidomide-based CRBN ligand or a VHL ligand. Potent and selective PROTAC-induced degradation of MDM2 was observed for the CRBN-MDM2 heterodimers. However notably, protein level of the hijacked CRBN or VHL ligases were not monitored. More recently, hetero-bifunctional VHL-CRBN PROTACs were also disclosed in a study recently published by Steinebach et al. Preferential degradation of CRBN over VHL was also observed by Steinebach et al., with their most potent compound (CRBN-6-5-5-VHL) being a conjugate of pomalidomide and VHL ligand via the terminal acetyl group, as with 14a, albeit with a different linker structure. Our study provides proof of principle for dimerizing two different E3 ligases as a novel approach to inducing one ligase to degrade the other one. The outcome of 'ligase versus ligase' PROTAC-mediated activity might be unpredictable a priori, but could reveal a new mechanism for proximity mediated hijacking between E3 ligases. Future work is warranted to interrogate many more combinations of E3 ligases and hetero-dimerizer compounds to bring E3 ligases together as a mechanism to induce their intracellular degradation. Given the number of E3 ligases predicted to function in cells (up to 600) this approach could speed up our ability to chemically intervene on E3 ligase themselves using targeted protein degradation, with both biological and therapeutic benefits.