PD and efficacy studies of KIN-8194 in ibrutinib-sensitive BTK^WT-expressing TMD-8 ABC DLBCL xenografted mice. PD studies showing the activity of HCK and BTK after oral administration of KIN-8194 in NOD-SCID mice subcutaneously xenografted with ibrutinib-sensitive BTK^WT TMD-8 ABC DLBCL cells. Phosflow plots for (A) pHCK^Y410 and (B) pBTK^Y223 in GFP⁺ TMD-8 tumor cells excised at 6 and 24 hours after oral administration of KIN-8194 at the indicated doses (n = 3 per group). (C) Efficacy studies in NOD-SCID mice (n = 8 per cohort) bearing ibrutinib-sensitive BTK^WT TMD-8 cells after daily oral administration of vehicle control, ibrutinib, A419259, or KIN-8194 at 50 mg/kg. Tumor volume (mm³) was measured twice per week and reported as the mean volume ± standard error of the mean (SEM). Treatment was stopped (indicated by green arrow) at day 42 and tumor volumes were monitored until day 113. (D) Tumor volume comparisons at day 33. P values for comparisons against mice treated with vehicle control are shown. (E) Survival curve estimations using the Kaplan-Meier method. The median survival (days) for cohorts were determined by using Prism software. P < .0001 for log-rank comparisons between cohorts. ****P < .0001.