Inhibitory effects of KW-2449 on BCR/ABL-positive leukemia cells. We compared inhibitory effects on wt (K562 and TCC-Y) and T315I-mutated (TCC-Y/sr) BCR/ABL-expressing human leukemia cells between KW-2449 and imatinib (IM). (A) In K562 cells, KW-2449 and IM equally decreased the phosphorylation levels of BCR/ABL and STAT5 and increased cleaved PARP. (B) In TCC-Y cells, IM decreased the phosphorylation levels of BCR/ABL and STAT5, but did not increase cleaved PARP. In contrast, KW-2449 decreased the phosphorylation levels of BCR/ABL and STAT5 and increased cleaved PARP. (C) In TCC-Y/sr cells, IM did not affect the phosphorylation levels of BCR/ABL and STAT5, whereas KW-2449 decreased both phosphorylation levels and increased cleaved PARP. (D) DNA contents were also compared between KW-2449 and IM treatments. IM increased the number of the G₁-arrested cells only in K562 cells. However, KW-2449 induced the G₂/M-arrested cells in K562, TCC-Y, and TCC-Y/sr cells. (E) We compared the antileukemic efficacy in NOD/SCID mice xenotransplanted with human CML in blast crisis cells harboring the T315I mutation after IM treatment. The treatment effects on the leukemia cells in PB are shown by the after/before BCR/ABL transcript ratio. After the treatment, the BCR/ABL transcript levels in PB increased to 3.391 plus or minus 1.071 and 1.927 plus or minus 0.332 times as much as those before the treatment in the vehicle- and IM-treated mice, respectively. In contrast, KW-2449 significantly decreased BCR/ABL transcript levels as to 0.553 ± 0.288 times as much as those before the treatment compared with the vehicle- and IM-treated mice (P = .001 and P = .003 by the unpaired t test, respectively). (F) Residual leukemia cells in femora were evaluated by the immunohistochemical staining with human CD45. KW-2449 more potently eradicated leukemia cells in BM than IM.