Targeting proteins for degradation by hijacking the ubiquitin-proteasome system with small molecules is a powerful modality of intervention into biology, and an emerging therapeutic strategy. A primary approach to targeted protein degradation involves the design of PROTACs (PROteolysis Targeting Chimeras). PROTACs are bifunctional compounds that form a ternary complex with a target protein of interest and an E3 ubiquitin ligase, such that the target protein is ubiquitinated by the hijacked E3 ligase and subsequently degraded by the proteasome. PROTACs are defined by a catalytic, sub-stoichiometric mode of action that can allow for rapid, profound and selective target depletion inside cells, and an extended duration of action, also in vivo. Because their mode of action differs from that of conventional inhibitors, the concentrations at which PROTACs exert degradation activity are often much lower than expected based on their dissociation constants with the target protein. Furthermore, PROTACs selectivity can be greater than the binding selectivity of the ligands alone, allowing to discriminate between highly similar proteins or isoforms in ways that are not possible with occupancy-based inhibitors. Within the past four years, potent and selective PROTACs have been designed to hijack either the von Hippel-Lindau (VHL) or cereblon (CRBN) E3 ligase against a target protein of interest. Targets that have been shown to be degraded by PROTACs include members of bromodomaincontaining proteins such as the BET proteins (Brd2, Brd3 and Brd4), amongst other epigenetic protein classes; protein kinases; as well as non-bromodomain and non-kinase target proteins. Recent progress in understanding principles of PROTAC mode of action, and demonstration of applicability across different target classes, suggest that PROTACs have the potential to target new protein families, including proteins that are difficult to block using current approaches. Clinical validation of small molecules inducing protein degradation is provided by recent discoveries on the molecular mechanism of thalidomide and related clinical anticancer immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide, which induce the proteasomal-dependent degradation of cancer-driving proteins. More recently, a PROTAC compound (ARV-110) that targets the androgen receptor for degradation has been announced as a clinical candidate. E3 ubiquitin ligases are key players in the ubiquitin proteasome pathway because they catalyse ubiquitination of substrate proteins. As important regulators of cellular ubiquitination, E3 ligases are emerging as attractive drug targets, particularly in cancer. However, E3 ligases have proven difficult to target using small molecule inhibitors. So far only few high-quality inhibitors have been developed, mainly against the ligases MDM2, VHL, and IAPs. E3 ligases lack deep binding sites to accommodate endogenous smallmolecule cofactors or substrates, as is the case for ATP in protein kinases. Targeting E3 ligases therefore requires disruption (or modulation) of protein-protein interactions. E3 ligase inhibitors face particular challenges: first, the difficulty to compete with high-affinity endogenous substrates, which increase in level as a result of E3 blockade; and second, the observation that small molecules that bind to E3 ligases may modulate the surface of the targeted E3 in such a way that new substrate proteins are recruited for degradation, as shown for the E3 ligases CRBN, and DCAF15. We hypothesized that the E3 ligases themselves might be hijacked against one another using a PROTAC approach, thus inducing E3 ligase degradation as opposed to E3 blockade. In 2017, we disclosed the first report of a small molecule dimerizer of an E3 ligase as a means to induce its own degradation, and approach that we called "homo-PROTAC". We designed bifunctional molecules made up of the same ligand for the ubiquitously expressed VHL protein, connected via a linker, that would induce VHL dimerization as the key step to trigger VHL ubiquitination and subsequent degradation. The best degrader, the symmetric homo-PROTAC CM11 (Figure ), dimerized VHL in vitro with high avidity (cooperativity) of ~20-fold, leading to potent, complete and prolonged degradation of VHL in different cell lines. With CM11, we confirmed the hypothesized mechanism and qualified a novel chemical probe degrader for VHL. Subsequently, the same idea was applied by Krönke, Gütschow and co-workers, who reported homo-PROTACs for the CRBN ligase, and showed compound 15a (CC15a in Figure ) to be the most active compound. As an extension of our homo-PROTAC approach, we envisaged that two different E3 ligases could be brought together using hetero-bifunctional PROTACs made of a ligand handle for one ligase and another handle for a different ligase. We hypothesized that with such compounds the two E3 ligases might be hijacked against one another, leading to two potential scenarios: 1) both ligases being degraded in cell; 2) one of the two being preferentially degradedresulting in one ligase 'winning' over the other one. In the present study, we describe the design, synthesis and cellular activity of VHL-CRBN heterodimerizing PROTACs, and interrogate the outcome of hijacking these two E3 ligases against each other.