Structural, thermodynamic and kinetic favorability of ternary complex formation are critical for efficient PROTAC mode of action . These factors are determined by neointeractions within the ternary complex, including between E3 ligase and target, similar to the mechanism of monovalent molecular glues. This results in stable, cooperative, and long-lived complexes which drive efficient catalytic ubiquitination . Such ternary complexdependent outcomes can be optimized through rational design . For compounds which do not have this, their window of degradation efficacy will be limited by the hook effect as nonproductive binary complexes with either the target or E3 ligase will more readily compete the ternary complex at higher PROTAC concentration (Fig. ) . In our studies with the trivalent PROTAC, we find that optimization of structural, energetic, and kinetic ternary complex parameters occurred from combined binding avidity and cooperativity in the process, resulting in stable biophysical recognition and prolonged cellular residence times (Fig. ). Our data suggests that it is this combination which increased most significantly the degradation activity, as the trivalent CRBN-based PROTACs, which we predict would also have avidity, were much less active. Indeed, more in-depth mechanistic experiments with representative CRBN-based trivalent PROTAC SIM4 showed that this compound, despite its ability to efficiently form ternary complexes, showed very low levels of BET family ubiquitination, and as a result induced only partial protein degradation (Extended Data Fig. ). For the VHL-based SIM1, an improvement in all the parameters with the trivalent PROTAC resulted in a vast expansion of the degradation window, from rapid rates of BET family loss at very low concentration to maximal degradation with minimal hook effect observed at concentration up to 30µM, which is 500,000-fold above the Dmax50. Some of these characteristics have been observed previously with bivalent PROTACs such as cooperative complexes with MZ1 and potent degradation with dBET-6 and ARV-771 , but the combination of these to achieve maximal favorability in the ternary complex to enhance degradation had not yet been shown.