KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation
KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation
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DOI：
10.1182/blood-2009-01-199307
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发表时间：
2009-08-20
期刊：
影响因子：
20.3
通讯作者：
Naoe, Tomoki
中科院分区：
文献类型：
--
作者：
Shiotsu, Yukimasa;Kiyoi, Hitoshi;Naoe, Tomoki
KW-2449是一种FLT 3、ABL、ABL-T315 I和Aurora激酶的多激酶抑制剂，正在研究用于治疗白血病患者。在这项研究中，我们研究了其对FLT 3激活，FLT 3野生型或伊马替尼耐药白血病细胞的抗白血病作用的可能作用模式。KW-2449通过抑制FLT 3激酶，对FLT 3突变的白血病细胞显示出强效的生长抑制作用，导致磷酸化FLT 3/STAT 5、G（1）阻滞和凋亡的下调。KW-2449的口服给药在FLT 3突变的异种移植模型中显示出剂量依赖性和显著的肿瘤生长抑制，具有最小的骨髓抑制。在FLT 3野生型人类白血病中，它诱导磷酸化组蛋白H3减少、G（2）/M阻滞和细胞凋亡。在伊马替尼耐药的白血病中，KW-2449通过同时下调BCR/ABL和Aurora激酶而有助于释放耐药性。此外，KW-2449的抗增殖活性在来自AML和伊马替尼耐药患者的原代样品中得到证实。KW-2449的抑制活性不受人血浆蛋白（如α 1-酸性糖蛋白）的影响。这些结果表明KW-2449通过几种作用机制对各种类型的白血病具有有效的生长抑制活性。我们的研究表明KW-2449具有显著的活性，并保证在FLT 3突变以及伊马替尼耐药突变的白血病患者中进行临床研究。（血。2009; 114：1607-1617）
KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wildtype, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G(1) arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wildtype human leukemia, it induced the reduction of phosphorylated histone H3, G(2)/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the anti-proliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as alpha 1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations. (Blood. 2009; 114: 1607-1617)