Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells.

نویسندگان

  • Ruriko Tanaka
  • Matthew S Squires
  • Shinya Kimura
  • Asumi Yokota
  • Rina Nagao
  • Takahiro Yamauchi
  • Miki Takeuchi
  • Hisayuki Yao
  • Matthias Reule
  • Tomoko Smyth
  • John F Lyons
  • Neil T Thompson
  • Eishi Ashihara
  • Oliver G Ottmann
  • Taira Maekawa
چکیده

Despite promising clinical results from imatinib mesylate and second-generation ABL tyrosine kinase inhibitors (TKIs) for most BCR-ABL(+) leukemia, BCR-ABL harboring the mutation of threonine 315 to isoleucine (BCR-ABL/T315I) is not targeted by any of these agents. We describe the in vitro and in vivo effects of AT9283 (1-cyclopropyl-3[5-morpholin-4yl methyl-1H-benzomidazol-2-yl]-urea), a potent inhibitor of several protein kinases, including Aurora A, Aurora B, Janus kinase 2 (JAK2), JAK3, and ABL on diverse imatinib-resistant BCR-ABL(+) cells. AT9283 showed potent antiproliferative activity on cells transformed by wild-type BCR-ABL and BCR-ABL/T315I. AT9283 inhibited proliferation in a panel of BaF3 and human BCR-ABL(+) cell lines both sensitive and resistant to imatinib because of a variety of mechanisms. In BCR-ABL(+) cells, we confirmed inhibition of substrates of both BCR-ABL (signal transducer and activator of transcription-5) and Aurora B (histone H3) at physiologically achievable concentrations. The in vivo effects of AT9283 were examined in several mouse models engrafted either subcutaneously or intravenously with BaF3/BCR-ABL, human BCR-ABL(+) cell lines, or primary patient samples expressing BCR-ABL/T315I or glutamic acid 255 to lysine, another imatinib-resistant mutation. These data together support further clinical investigation of AT9283 in patients with imatinib- and second-generation ABL TKI-resistant BCR-ABL(+) cells, including T315I.

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منابع مشابه

MYELOID NEOPLASIA Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL–positive leukemic cells

1Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; 2Astex Therapeutics Ltd, Cambridge, United Kingdom; 3Division of Hematology, Respiratory Medicine, and Oncology, Saga University, Saga, Japan; 4Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; and 5Department of Hematology, Johann Wolfgang Goethe U...

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عنوان ژورنال:
  • Blood

دوره 116 12  شماره 

صفحات  -

تاریخ انتشار 2010