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Blood, 20 August 2009, Vol. 114, No. 8, pp. 1607-1617. Prepublished online as a Blood First Edition Paper on June 18, 2009; DOI 10.1182/blood-2009-01-199307. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-01-199307v1 114/8/1607    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Shiotsu, Y. Articles by Naoe, T. PubMed PubMed Citation Articles by Shiotsu, Y. Articles by Naoe, T. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation Yukimasa Shiotsu1,*, Hitoshi Kiyoi2,*, Yuichi Ishikawa2,3, Ryohei Tanizaki3, Makiko Shimizu1, Hiroshi Umehara1, Kenichi Ishii1, Yumiko Mori2,3, Kazutaka Ozeki2, Yosuke Minami3, Akihiro Abe3, Hiroshi Maeda4, Tadakazu Akiyama1, Yutaka Kanda1, Yuko Sato5, Shiro Akinaga4, and Tomoki Naoe3 1 Fuji Research Park, Kyowa Hakko Kirin, Shizuoka; 2 Department of Infectious Diseases and 3 Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya; 4 Clinical Development Division, Kyowa Hakko Kirin, Tokyo; and 5 Research Institute, International Medical Center of Japan, Tokyo, Japan KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G1 arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G2/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as 1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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