Figure 6. Models of trivalent ternary complex formations and advantages over monovalent and bivalent compounds.

a) Proposed mechanism for the formation of a 1:1:1 ternary complex between trivalent PROTAC, VHL and BET protein. Preferential initial binding of the PROTAC to BD2 of BRD4 is followed by conformational change and bidentate binding to BD1. Avidity and cooperativity contribute to formation of a highly stable ternary complex with enhanced residence time at extraordinarily low concentrations of SIM1. b) Shown are different types of degrader-induced ternary complexes, depicted at their varying extents as a function of degrader concentration. A trivalent complex combining avidity with cooperativity shows the highest and most sustained levels of ternary complex formation, with a minimized hook effect. A cooperative bivalent PROTAC complex is next, followed by a non-cooperative bivalent complex. Lastly, the ternary complex induced by molecular glue compounds is shown, which reaches a plateau and unlike PROTACs are not predicted to experience the competitive hook effect at higher concentrations. c) A general model for trifunctional compound-induced ternary complex utilizing a compound with three different warheads (or ligands) to recruit together three distinct protein.