SIM1 is a potent von Hippel-Lindau (VHL)-based trivalent PROTAC capable of degradation for all BET family members, with preference for BRD2 degradation (IC50=1.1 nM; Kd=186 nM). SIM1 shows sustained anti-cancer activity[1].
SIM1 (1 nM; 30 hours; MV4-11 cells) results in measurable cellular death after 6 hours[1].SIM1 (1 µM; 4 hours; HEK293 cells) degrades BET proteins[1].SIM1 induces conformational changes upon binding to the BET protein to simultaneously engage with high avidity both its bromodomains in a cis intramolecular fashion. SIM1 engages BD1 and BD2 intramolecularly and forms a 1:1:1 ternary complex with VHL and BRD4[1].
[1]. Satomi Imaide, et al. Trivalent PROTACs enhance protein degradation through cooperativity and avidity. Biological and Medicinal Chemistry.