Sonrotoclax is more efficacious than venetoclax in both cancer cells and xenograft mouse models. (A) Cell viability inhibition was measured using a CellTiter-Glo luminescence assay. (B) Disruption of the BCL2:BIM complex was detected by a cell-based competitive Meso Scale Discovery (MSD) assay. (C) The activation of caspase-3 and caspase-7 (caspase-3/7) was measured in RS4;11 cells with a Caspase-Glo kit. Annexin V⁺ cells were quantified by FITC annexin V staining and FACS analysis in RS4;11 cells. The accumulation of sub-G0/G1 in RS4;11 cells was assessed by PI staining and FACS analysis. The data are presented as the mean values ± SDs for 3 independent experiments, with representative plots shown in the figures. EC₅₀, half maximal effective concentration. (D) MV4-11 (AML), MAVER-1 (MCL), and Toledo (DLBCL) cells were treated with serial dilutions of sonrotoclax or venetoclax for 2 days, and cell viability inhibition was measured by a CellTiter-Glo luminescence assay. IC₅₀ values are presented as the mean values ± SDs for 3 independent experiments. (E-G) The in vivo antitumor activity of sonrotoclax and venetoclax was evaluated in human RS4;11 (E), MAVER-1 (F), and Toledo (G) xenograft models. Mice were treated with sonrotoclax or venetoclax once daily at the indicated doses by oral gavage. The tumor volumes are presented as the mean values ± standard error of the mean (SEMs) of 8 (E) or 10 (F-G) mice in each group; ∗∗∗∗P < .0001. EC₅₀, half maximal effective concentration, FACS, fluorescence-activated cell sorting; FITC, fluorescein isothiocyanate; mpk, milligrams per kilogram; PI, propidium iodide.