S63845 has antiproliferative activity in lymphoma cells and synergizes with venetoclax. (A) Heat map summarizing the IC₅₀ (mean ± standard error of the mean [SEM]) in µM of S63845 and venetoclax in 14 lymphoma cell lines with the following subtypes: activated B-cell (ABC) DLBCL, germinal center B-cell (GCB) DLBCL, double-hit lymphoma (DHL), and mantle cell lymphoma (MCL). Cells were incubated with increasing concentrations of drug for 72 hours. Data represent the mean of 3 separate experiments. Cell viability was assessed by CellTiter-Glo. Sensitive, IC₅₀ <0.1 µM; moderately sensitive, IC₅₀ between 0.1 and 1 µM; resistant, IC₅₀ >1 µM. (B) Dot plots quantifying MCL1, BCL2, BCL-xL, and BIM protein expression from western blot in supplemental Figure 2A in the 4 cell lines most resistant (Res) (U-2932, HBL-1, Ri-1, and Maver-1) and sensitive (Sen) (U-2973, OCI-LY19, Mino, and SU-DHL-6) to S63845. Each point represents the protein:β-actin ratio in a cell line. Error bars represent SD from 4 different cell lines listed above. Statistical significance was measured by an unpaired Student t test. (C) Heat map summarizing the effect of combinations of varying concentrations of S63845 and venetoclax on cell viability in the indicated cell lines as assessed by the CellTiter-Glo assay. Combination responses are examined in a 5 × 5 viability matrix after 24 hours of treatment. Percentage of cell viability is depicted in a colorimetric scale from black (high) to white (low) normalized to dimethyl sulfoxide control. Values are the mean of 3 separate experiments. (D) Box plot graph summarizing the results of treatment with combined S63845 and venetoclax for 24 hours in the 3 cell lines most resistant to S63845 (Ri-1, HBL-1, and U-2932) and venetoclax (TMD8, Z-138, and Jeko-1). The y-axis depicts the log-odds that indicate the ratio between observed and expected inhibition on a log scale. Log-odds >0 signify antagonism, log-odds of 0 signify an additive effect, and log-odds <0 (area below gray line) indicate synergy between the 2 drugs. Cell viability was assessed by CellTiter-Glo. All data points represent the mean of 3 separate experiments. ***P < .001; **P < .01; *P = .02.