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

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

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Abstract

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.

Original languageEnglish
Pages (from-to)2089-2095
Number of pages7
JournalBlood
Volume116
Issue number12
DOIs
Publication statusPublished - Sep 23 2010

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Tanaka, R., Squires, M. S., Kimura, S., Yokota, A., Nagao, R., Yamauchi, T., ... Maekawa, T. (2010). Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells. Blood, 116(12), 2089-2095. https://doi.org/10.1182/blood-2009-03-211466