ACBI2

Note should be taken that the oral dose shown above is for PK studies only. In the manuscript, efficacy and tolerability in a xenograft model at a dose of 80 mg/kg are shown, presumably to achieve more complete degradation of SMARCA2 as shown in a preliminary PD experiment.

While ACBI2 should be considered a high quality degrader of SMARCA2 in cells, the use of this tool requires caution. The authors show that 2/4 selectivity can vary widely between cell lines and thus time points and concentrations may need to be adjusted to maintain a desirable window. A dose response between 1 and 100 nM seems sensible and SMARCA2/4 levels should be verified for each cell lines tested. While this tool appears suitable for in vivo studies with oral dosing, the level of SMARCA2/4 degradation and its time course is not robustly established and will again likely vary depending on the model. For example in the A549 model a non-complete SMARCA2 degradation was seen in a 48 hour PKPD experiment whereas at 21 days a complete elimination of SMARCA2 was seen; the effect of ACBI2 on SMARCA4 in a 21-day in vivo setting has not been studied. In vivo studies should be in a dose response setting including doses lower than 80 mpk. Data interpretation of ACBI2 experiments should always be accompanied by the determination of SMARCA protein levels.