Bivalent PROTACs {work|function|perform|operate} drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary {complex|complicated}. We hypothesized that {increasing|growing|escalating|rising} binding valency {within|inside} a PROTAC could enhanced degradation. {Here|Right here}, we {designed|developed|created|made} trivalent PROTACs consisting of a bivalent BET inhibitor and an E3 ligand, tethered {via|by way of|through|by means of} a branched linker. We identified VHL-based SIM1 as a low picomolar BET degrader, with preference for BRD2. {Compared to|In comparison to|In comparison with|When compared with} bivalent PROTACs, SIM1 showed {more|much more|a lot more|far more|additional|extra} sustained and {higher|greater|larger} degradation efficacy, which led to {more|much more|a lot more|far more|additional|extra} potent anti-cancer activity. Mechanistically, SIM1 simultaneously engages with {high|higher} avidity {both|each} BET bromodomains {in a|inside a|within a} cis intramolecular {fashion|style} and {forms|types} a 1:1:1 ternary {complex|complicated} with VHL exhibiting {positive|good|optimistic|constructive} cooperativity and {high|higher} cellular stability with prolonged residence time. Collectively, our {data|information} {along with|together with|in addition to|as well as|in conjunction with} favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities {can be|may be|could be|might be|is often|is usually} an enabling {strategy|technique|method|approach|tactic} for advancing functional outcomes. Potassium trifluoro(vinyl)borate Purity Ursocholic acid Chemscene PMID:24118276
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