We next sought to further understand the SIM1 degradation preference for BRD2 compared to other PROTACs. Live-cell kinetic degradation dose response profiles were performed with the bivalent BET degrader ARV-771 (10) using the CRISPR HiBiT-BET cell lines (Extended Data Fig. ) and degradation parameters were quantitated and compared with those previously determined for MZ1 and SIM1 (Fig. ). Shown in Fig. increased degradation potency for BRD2 as compared to ARV-771 and MZ1, respectively (Fig. ). As enhanced degradation rates tend to correlate with enhanced ubiquitination, cellular studies were performed to monitor the kinetics of ubiquitination of BET proteins using bioluminescence resonance energy transfer (NanoBRET) assays consisting of the HiBiT-BET CRISPR cell lines expressing fluorescently labelled HaloTag-Ubiquitin . Shown in Fig 2d , kinetic increases in cellular ubiquitination were greater for BRD2 as compared to BRD3 and BRD4 after a 10nM SIM1 treatment. These same trends were observed at 100nM SIM1 concentration and comparison to MZ1 (Fig. ), revealing that SIM1 led to higher levels of ubiquitination of all BET family members (Extended Data Fig. ), with the greatest difference observed for BRD2.