The study presented here finds inspiration from an often-used strategy for improvement of compound efficacy, i.e. increasing binding valency, and has leveraged this for improved PROTAC-mediated protein degradation. Our work qualifies the novel trivalent PROTAC SIM1 as a profoundly potent and fast degrader of BET proteins. Our biological and mechanistic investigation with SIM1 provides proof-of-concept for augmenting the valency of degraders as an advantageous strategy to enhance their mode of action by positively impacting the ternary complex. SIM1 bound intramolecularly the BET protein in a cis-fashion to both BD1 and BD2, inducing a conformational change, to then form a 1:1:1 complex (Fig. ). Further investigation with BD1 or BD2 mutants suggested there is preferred BD2 binding of SIM1 with BRD4 (Fig. ). Interestingly BRD2 was found in a series of orthogonal assays to show the most favorable ternary complex formation and prolonged residence time, the most robust level of ubiquitination, and correspondingly the fastest and highest level of degradation amongst the family members with SIM1. This is unprecedented preference amongst known BET PROTAC degraders. We cannot exclude the possibility that the structural change induced by SIM1 better positions BRD2 in a more favourable state for more productive ubiquitination, as compared to BRD3 or BRD4.