Identification of a highly efficient dual type I/II FMS-like tyrosine kinase inhibitor that disrupts the growth of leukemic cells
Identification of a highly efficient dual type I/II FMS-like tyrosine kinase inhibitor that disrupts the growth of leukemic cells
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DOI：
10.1016/j.chembiol.2021.10.011
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发表时间：
2022-03-17
影响因子：
8.6
通讯作者：
Kraemer, Oliver H.
中科院分区：
文献类型：
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作者：
Beyer, Mandy;Henninger, Sven J.;Kraemer, Oliver H.
fms样酪氨酸激酶-3 （FLT3）的内部串联重复（ITDs）与预后不良的急性髓系白血病（AML）有因果关系。现有FLT3抑制剂（FLT3i）优先靶向FLT3的非活性或活性构象。此外，它们共同靶向正常造血的激酶，容易受到治疗相关酪氨酸激酶结构域（TKD） FLT3突变的影响，或者缺乏低纳摩尔活性。我们发现酪氨酸激酶抑制剂marbotinib抑制FLT3-ITD的磷酸化和FLT3-ITD的永久性和原发性AML细胞的生长。这也适用于携带FLT3-ITD/TKD突变体的白血病细胞，这些突变体赋予临床使用的FLT3i耐药性。马博替尼对FLT3表现出高选择性，并改变信号传导，使人想起FLT3- itd的遗传消除。分子对接表明，马博替尼在FLT3的非活性构象和活性构象中以相反的方向匹配。水溶性马替尼-氨基甲酸酯可显著延长flt3驱动白血病小鼠的生存期。Marbotinib是一种纳米摩尔的下一代FLT3i，代表了混合抑制原理。
Internal tandem duplications (ITDs) in the FMS-like tyrosine kinase-3 (FLT3) are causally linked to acute myeloid leukemia (AML) with poor prognosis. Available FLT3 inhibitors (FLT3i) preferentially target inactive or active conformations of FLT3. Moreover, they co-target kinases for normal hematopoiesis, are vulnerable to therapy-associated tyrosine kinase domain (TKD) FLT3 mutants, or lack low nanomolar activity. We show that the tyrosine kinase inhibitor marbotinib suppresses the phosphorylation of FLT3-ITD and the growth of permanent and primary AML cells with FLT3-ITD. This also applies to leukemic cells carrying FLT3-ITD/TKD mutants that confer resistance to clinically used FLT3i. Marbotinib shows high selectivity for FLT3 and alters signaling, reminiscent of genetic elimination of FLT3-ITD. Molecular docking shows that marbotinib fits in opposite orientations into inactive and active conformations of FLT3. The water-soluble marbotinib-carbamate significantly prolongs survival of mice with FLT3-driven leukemia. Marbotinib is a nanomolar next -generation FLT3i that represents a hybrid inhibitory principle.