Studies assessing synergistic interactions of KIN-8194 and the BCL_2 inhibitor venetoclax. (A) In vitro studies assessed for synergistic interactions of KIN-8194 and venetoclax in native (untransduced), BTK^WT-, and BTK^Cys481Ser-expressing MYD88-mutated BCWM.1 WM and TMD-8 ABC DLBCL cells. The combination index (CI) and normalized isobologram analyses are depicted. CI <1 (indicated in shades of red) or the dots under the oblique line in the isobologram plots indicate a synergistic effect for the combination. (B) Efficacy studies in NOD-SCID mice (n = 8 per cohort) bearing ibrutinib-resistant BTK^Cys481Ser-expressing TMD-8 cells after daily oral administration of vehicle control, venetoclax (50 mg/kg), KIN-8194 (30 mg/kg), or the combination of venetoclax (50 mg/kg) and KIN-8194 (30 mg/kg). Tumor volume (mm³) was measured twice per week and reported as the mean volume ± SEM. (D) Tumor volume comparisons at day 22. P values are for cohort comparisons. (E) Survival curve estimations using the Kaplan-Meier method. Prism software was used to determine the median survival in days for cohorts. P = .002 for log-rank comparisons between cohorts.