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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3948-3954.
Prepublished online as a Blood First Edition Paper on August 16, 2005; DOI 10.1182/blood-2005-06-2209.
 Previous Article | Next Article 
Submitted June 2, 2005
Accepted August 9, 2005
NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia
Shinya Kimura*, Haruna Naito, Hidekazu Segawa, Junya Kuroda, Takeshi Yuasa, Kiyoshi Sato, Asumi Yokota, Yuri Kamitsuji, Eri Kawata, Eishi Ashihara, Yohei Nakaya, Haruna Naruoka, Tatsushi Wakayama, Kimio Nasu, Tetsuo Asaki, Tomoko Niwa, Kazuko Hirabayashi, and Taira Maekawa
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan
* Corresponding author; email: shkimu{at}kuhp.kyoto-u.ac.jp.
Though the Abl tyrosine kinase inhibitor imatinib mesylate has improved the treatment of 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 25-55 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 Ph+ leukemia.
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