PD and efficacy studies of KIN-8194 in ibrutinib-resistant BTK^Cys481Ser-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-resistant BTK^Cys481Ser 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-resistant BTK^Cys481Ser expressing TMD-8 cells after daily oral administration of vehicle control, ibrutinib (50 mg/kg), or KIN-8194 (50 or 75 mg/kg). Tumor volume (mm³) was measured twice per week and reported as the mean volume ± SEM. (D) Tumor volume comparisons at day 29. 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. Mantel-Cox long-rank P value of .0007 is for comparisons between cohorts. *P < .05; **P < .01; ***P < .005; ****P < .0001.