Efficacy of CYT387 against JAK2-dependent malignancy in vivo. (A) Balb/c mice were administered CYT387 by oral gavage and pharmacokinetics were measured by analysis of plasma concentrations at indicated time points. Values represent mean ± SEM. (n = 3) (B) Balb/c mice were subjected to bone marrow transplantation with bone marrow donor cells retrovirally transduced to express JAK2V617F. Thirty-four days after transplantation, mice exhibited symptoms of MPN as measured by elevated white blood cell counts and hematocrit. Mice were divided into 3 groups and initiated on twice daily oral gavage administration of vehicle control, 25 mg/kg CYT387, or 50 mg/kg CYT387 (n = 12 per group). White blood cell (WBC) count of mice was monitored weekly for 83 days after bone marrow transplantation. (C) Mice were treated as in panel B and hematocrit levels (HCT) of mice were monitored weekly for 83 days after bone marrow transplantation. (D) Mice were treated as in panel B and the percentage of granulocytes in the peripheral blood of mice was monitored weekly for 83 days after bone marrow transplantation. (E) Mice were treated as in panel B and percentage of lymphocytes in the peripheral blood of mice was monitored weekly for 83 days after bone marrow transplantation. (F) Mice were treated as in panel B and the spleen weight of 3 mice was measured at the start of treatment and the spleen weight of all mice was measured at the end of treatment. For comparison purposes, spleen weight from normal mice is included. For panels B through F, values represent mean ± SEM, *P < .05 in a t test comparing 25 mg/kg or 50 mg/kg treatment groups with the 0 mg/kg vehicle control. The gray box indicates the normal range in mice. The arrow indicates initiation of CYT387 treatment.
