NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia
NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia
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DOI：
10.1182/blood-2005-06-2209
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发表时间：
2005-12-01
期刊：
影响因子：
20.3
通讯作者：
Maekawa, T
中科院分区：
文献类型：
--
作者：
Kimura, S;Naito, H;Maekawa, T
尽管Abelson（Abl）酪氨酸激酶抑制剂甲磺酸伊马替尼改善了断点簇区域-Abl（Bcr-Abl）阳性白血病的治疗，但在晚期疾病患者中经常报告耐药。虽然几种Src抑制剂比伊马替尼更有效，同时抑制林恩，其过表达与伊马替尼耐药性相关，但这些抑制剂的特异性低于伊马替尼。我们已经确定了一种特异性的双重抑制剂NS-187（在其他地方称为CNS-9），其体外效力是伊马替尼的25至55倍。NS-187在抑制携带Bcr-Abl的肿瘤生长方面的有效性也是伊马替尼的至少10倍，并且显著延长了携带这种肿瘤的小鼠的存活期。NS-187的抑制作用延伸到13个Bcr-Abl蛋白中的12个，其激酶结构域中具有突变，但不延伸到T315 l。NS-187还抑制林恩而不影响Src、Blk或Yes的磷酸化。这些结果表明，NS-187可能是一个潜在的有价值的新的药物，以打击伊马替尼耐药费城阳性（Ph+）白血病。
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 T315l. 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.