3,4-Diarylmaleimides—a novel class of kinase inhibitors—effectively induce apoptosis in FLT3-ITD-dependent cells
3,4-Diarylmaleimides—a novel class of kinase inhibitors—effectively induce apoptosis in FLT3-ITD-dependent cells
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3,4-二芳基马来酰亚胺——一类新型激酶抑制剂——有效诱导 FLT3-ITD 依赖性细胞凋亡
DOI：
10.1007/s00277-011-1311-3
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发表时间：
2012
影响因子：
3.5
通讯作者：
Fischer T
中科院分区：
文献类型：
--
作者：
Heidel FH;Mack TS;Razumovskaya E;Blum MC;Lipka DB;Ballaschk A;Kramb JP;Plutizki S;Rönnstrand L;Dannhardt G;Fischer T
FLT 3激酶已成为AML中有吸引力的药物靶标，高达30%的病例携带内部串联重复（ITD）突变。对于这些，给予更差的预后和降低的总生存期，几种FLT 3酪氨酸激酶抑制剂（TKI）目前正在临床试验中进行测试。然而，当使用这些药物作为单药治疗时，出现了缓解持续时间短和TKI耐药发生率高的问题。在这里，我们研究了一类新的酪氨酸激酶抑制剂，3，4-二芳基马来酰亚胺，其对突变的FLT 3激酶的疗效的两个成员。这些化合物以ATP竞争性方式抑制FLT 3激酶，并有效抑制下游靶标的磷酸化。3，4-二芳基马来酰亚胺（DHF 125和150）在低微摩尔浓度下诱导FLT 3-ITD依赖性细胞系和患者胚细胞凋亡。它们保留在暴露细胞的细胞质中超过24小时，并与化疗和米多替林协同作用。与米多替林相比，两种3，4-二芳基马来酰亚胺均显示出对FLT 3-ITD相关激酶在不同酪氨酸残基处的自磷酸化的抑制。总之，这组新的化合物显示出对FLT 3激酶的不同抑制模式，并显示出进一步临床开发的前景。目前，正在进行小鼠模型中评价毒性和阐明确切结合机制的实验，以促进潜在的临床应用。
FLT3 kinase has become an attractive drug target in AML with up to 30% of cases harboring internal-tandem-duplication (ITD) mutations. For these, conferring a worse prognosis and decreased overall survival, several FLT3 tyrosine kinase inhibitors (TKIs) are currently being tested in clinical trials. However, when using these drugs as monotherapy, the problem of short duration of remissions and high incidence of TKI resistance has emerged. Here, we investigated two members of a novel class of tyrosine kinase inhibitors, 3,4-diarylmaleimides, for their efficacy on mutated FLT3 kinase. These compounds inhibit FLT3 kinase in an ATP-competitive manner and effectively inhibit phosphorylation of downstream targets. 3,4-Diarylmaleimides (DHF125 and 150) induce apoptosis in FLT3-ITD-dependent cells lines and patient blasts at low micromolar concentrations. They are retained in the cytoplasm of exposed cells for more than 24 h and synergize with chemotherapy and midostaurin. Both 3,4-diarylmaleimides show inhbition of FLT3-ITD-related kinase autophosphorylation at distinct tyrosine residues when compared to midostaurin. In conclusion, this novel group of compounds shows differential inhibition patterns with regard to FLT3 kinase and displays a promising profile for further clinical development. Currently, experiments evaluating toxicity in murine models and unraveling the exact binding mechanism are under way to facilitate a potential clinical application.
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影响因子：
11.4
作者：
Huber, S.;Oelsner, M.;Ringshausen, I.
通讯作者：
Ringshausen, I.
影响因子：
20.3
作者：
Godwin, JE;Kopecky, KJ;Appelbaum, FR
通讯作者：
Appelbaum, FR
致癌突变体的转化和 FLT3 野生型的配体依赖性激活需要酪氨酸残基 589 和 591
影响因子：
11.5
作者：
S. Vempati;C. Reindl;U. Wolf;Ruth Kern;Konstantin Petropoulos;V. Naidu;C. Buske;W. Hiddemann;Tobias M. Kohl;K. Spiekermann
通讯作者：
K. Spiekermann
影响因子：
158.5
作者：
MAYER, RJ;DAVIS, RB;FREI, E
通讯作者：
FREI, E
影响因子：
20.3
作者：
Rocnik, Jennifer L.;Okabe, Rachel;Gilliland, D. Gary
通讯作者：
Gilliland, D. Gary