Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase
Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase
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DOI：
10.1038/sj.leu.2403736
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发表时间：
2005-06-01
期刊：
影响因子：
11.4
通讯作者：
Hirai, H
中科院分区：
文献类型：
--
作者：
Komeno, Y;Kurokawa, M;Hirai, H
Fms 样酪氨酸激酶 3 (FLT3)（一种 III 型受体酪氨酸激酶）近膜结构域中的组成型活性内部串联重复 (ITD) 是与急性髓系白血病相关的最常见分子缺陷。它的存在导致接受常规化疗的急性髓系白血病患者预后不佳。因此，FLT3-ITD 被认为是新型治疗方式的有吸引力的分子靶标。我们在这里描述了 Ki23819 作为一种新型 FLT3 抑制剂的鉴定和表征。 Ki23819 抑制表达 FLT3-ITD 的人白血病细胞系的增殖并诱导细胞凋亡。 Ki23819 对 MV4-11 细胞的生长抑制作用优于另一种 FLT3 抑制剂 SU11248（IC50 < 1 vs 3 - 10 nM）。 Ki23819 比野生型 FLT3 更有效地抑制 FLT3-ITD 的自磷酸化。 FLT3-ITD 依赖性下游信号蛋白 ERK 和 STAT5 的激活也在相似的浓度范围内受到抑制。因此，Ki23819 是一种有效的 FLT3 体外抑制剂。
Constitutively active internal tandem duplication ( ITD) in the juxtamembrane domain of Fms- like tyrosine kinase 3 ( FLT3), a type III receptor tyrosine kinase, is the most common molecular defect associated with acute myeloid leukemia. Its presence confers a poor outcome in patients with acute myeloid leukemia who receive conventional chemotherapy. FLT3- ITD has therefore been considered to be an attractive molecular target for a novel therapeutic modality. We describe here the identification and characterization of Ki23819 as a novel FLT3 inhibitor. Ki23819 suppressed proliferation and induced apoptosis of FLT3- ITD- expressing human leukemia cell lines. The growth-inhibitory effect of Ki23819 on MV4- 11 cells was superior to that of SU11248, another FLT3 inhibitor ( IC50 < 1 vs 3 - 10 nM). Ki23819 inhibited the autophosphorylation of FLT3- ITD more efficiently than that of wild- type FLT3. FLT3- ITD- dependent activation of the downstream signaling proteins ERK and STAT5 was also inhibited within similar concentration ranges. Thus, Ki23819 is a potent in vitro inhibitor of FLT3.