Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that bridge a target protein to a ubiquitin E3 ligase to allow for poly-ubiquitination and proteasomal degradation of the target. 1-4 This modality of pharmacology features catalytic sub-stoichiometric mode of action, which brings benefits including lower doses and more durable effects compared to occupancy-based inhibitors that must occupy a functional site on the target protein to block its function. 5 PROTACs typically consist of a ligand for a target protein, connected by a chemical linker, to another ligand for an E3 ligase. This enables simultaneous recruitment and formation of a 1:1:1 ternary complex of a single molecule of target protein, the PROTAC and a single molecule of E3 ligase component. Most often, the recruited E3 ligases are either cereblon (CRBN) or von Hippel-Lindau (VHL). 6 Despite the advantages and remarkable successes achieved, it can be challenging to design PROTACs efficiently, often requiring extensive chemical optimization for the degradation of the target protein. 7-9 We and others became intrigued by the possibility that augmenting the valency of PROTACs might offer advantages by leveraging the principles and benefits of multi-targeting poly-pharmacology and/or avidity. 10 In a first foray of such approach, our group developed the concept of trivalent PROTACs and exemplified this with molecules embodying two ligands that can simultaneously bind to two sites/domains of the same target protein (rather than two different targets). Trivalent PROTAC SIM1 connected a single VHL ligand to two instances of a Bromo-and Extra-Terminal (BET) domain protein ligand, joined via a trifunctional linker. 11 SIM1 effectively and durably degrades BET proteins with picomolar degradation potency, without any detectable hook effect up to micromolar concentrations, due to the combined avidity of a simultaneous cis-engagement of both BET bromodomains, and the cooperativity of the VHL-BET bromodomain system. 11 Subsequently, others have developed multifunctional PROTACs capable of degrading, more than one target at the same time, through conjugation of ligands for two different target proteins to a single E3 ligase ligand. 12 Based on the success of SIM1, we wanted to understand whether recruiting two different E3 ligases (e.g. CRBN and VHL) simultaneously to the same target protein would have a synergistic effect on target protein degradation. We reasoned that such an approach could maximize the probability and efficacy of target protein degradation attained by a single PROTAC molecule, and minimize dependency on a single E3 ligase, a known Achilles' heel of PROTAC's mode of action, leading to mechanisms of cellular resistance to targeted protein degradation. 13-15 We therefore envisaged trifunctional or multifunctional molecules composed of one ligand for VHL, one ligand for CRBN, and one or more instances of target protein binding ligands. Such "hetero-multivalent" PROTACs would combine the ubiquitination activity from each E3 ligase, circumventing potential limitations of using two heterobivalent PROTAC molecules which would instead compete for binding to the same target protein. Here we provide proof-of-concept of this strategy with heteromultivalent molecules designed to simultaneously recruit VHL and CRBN to BET bromodomains.