SIM1

SIM1 is suitable for use to study intracellular degradation of BET proteins, and to produce a trivalent PROTAC with enhanced target degradation.

SIM1, a PROTAC degrader, is a highly potent bromo and extra terminal (BET) protein degrader (BRD2/3/4 Dmax50 = 57.3/413.9/96.3 pM post 22h using HEK293 expressing respective BRD; BRD2/3/4 λmax/h = 2.8/1.2/1.9 nM) that corresponds to a trivalent chimera composed of a Von Hippel Lindau (VHL) E3 ligase-targeting ligand linked to two molecules of BET inhibitor (+)-(S)-JQ1. Compared to bivalent degraders, SIM1 shows higher and more sustained degradation efficacy by simultaneously engaging two BET bromodomains with high avidity in a cis intramolecular fashion, exhibiting positive cooperativity, leading to more potent anticancer activity (MV4;11 AML viability IC50 = 1.1 nM/SIM1 vs 11.3 nM/MZ1 post 48h treatment). SIM1 is found to interact with the BD2 and BD1 bromodomains of BRD4, creating a ternary complex with VHL and BRD4. This interaction increases target binding valency and extends the duration of specific molecular interactions with the target.