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

研究成果: ジャーナルへの寄稿記事

48 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)2089-2095
ページ数7
ジャーナルBlood
116
発行部数12
DOI
出版物ステータス出版済み - 9 23 2010

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Phosphotransferases
Isoleucine
Threonine
Mutation
Protein-Tyrosine Kinases
Aurora Kinase B
Aurora Kinase A
Cells
STAT5 Transcription Factor
Janus Kinase 2
Cell Line
Protein Kinase Inhibitors
Histones
Lysine
Urea
Glutamic Acid
Leukemia
Imatinib Mesylate
1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
Substrates

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

これを引用

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

Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells. / Tanaka, Ruriko; Squires, Matthew S.; Kimura, Shinya; Yokota, Asumi; Nagao, Rina; Yamauchi, Takahiro; Takeuchi, Miki; Yao, Hisayuki; Reule, Matthias; Smyth, Tomoko; Lyons, John F.; Thompson, Neil T.; Ashihara, Eishi; Ottmann, Oliver G.; Maekawa, Taira.

:: Blood, 巻 116, 番号 12, 23.09.2010, p. 2089-2095.

研究成果: ジャーナルへの寄稿記事

Tanaka, R, Squires, MS, Kimura, S, Yokota, A, Nagao, R, Yamauchi, T, Takeuchi, M, Yao, H, Reule, M, Smyth, T, Lyons, JF, Thompson, NT, Ashihara, E, Ottmann, OG & Maekawa, T 2010, 'Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells', Blood, 巻. 116, 番号 12, pp. 2089-2095. https://doi.org/10.1182/blood-2009-03-211466
Tanaka R, Squires MS, Kimura S, Yokota A, Nagao R, Yamauchi T その他. Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells. Blood. 2010 9 23;116(12):2089-2095. https://doi.org/10.1182/blood-2009-03-211466
Tanaka, Ruriko ; Squires, Matthew S. ; Kimura, Shinya ; Yokota, Asumi ; Nagao, Rina ; Yamauchi, Takahiro ; Takeuchi, Miki ; Yao, Hisayuki ; Reule, Matthias ; Smyth, Tomoko ; Lyons, John F. ; Thompson, Neil T. ; Ashihara, Eishi ; Ottmann, Oliver G. ; Maekawa, Taira. / Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells. :: Blood. 2010 ; 巻 116, 番号 12. pp. 2089-2095.
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AU - Yokota, Asumi

AU - Nagao, Rina

AU - Yamauchi, Takahiro

AU - Takeuchi, Miki

AU - Yao, Hisayuki

AU - Reule, Matthias

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AU - Lyons, John F.

AU - Thompson, Neil T.

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