NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia

DOI PDF 被引用文献31件
  • Shinya Kimura
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Haruna Naito
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Hidekazu Segawa
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Junya Kuroda
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Takeshi Yuasa
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Kiyoshi Sato
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Asumi Yokota
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Yuri Kamitsuji
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Eri Kawata
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Eishi Ashihara
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Yohei Nakaya
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Haruna Naruoka
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Tatsushi Wakayama
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Kimio Nasu
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Tetsuo Asaki
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Tomoko Niwa
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Kazuko Hirabayashi
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.
  • Taira Maekawa
    From the Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; and Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Kyoto, Japan.

抄録

<jats:p>Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region–Abl (Bcr-Abl)–positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl–bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315I. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia.</jats:p>

収録刊行物

  • Blood

    Blood 106 (12), 3948-3954, 2005-12-01

    American Society of Hematology

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