Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order too optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD.

FLT3受体酪氨酸激酶（RTK）的突变体在近膜结构域（FLT3-ITD）中有重复，可作为急性髓细胞性白血病（AML）的驱动器。FLT3-ITD的有效酪氨酸激酶抑制剂（TKi）进入临床试验，由于出现了耐药性继发性AML克隆，因此显示出有希望的但短暂的成功。针对FLT3-ITD的药物的进一步警告是正常造血所需的其他RTK的共同靶向。这是很经常观察到的。因此，新型药物对于有效和安全地治疗AML是必要的。最近发现双（1 H-吲哚-2-基）甲烷酮可以抑制FLT3和PDGFR激酶。为了也优化这些试剂，我们合成了具有各种取代基的这些甲烷酮的新型衍生物。甲酮16其氨基甲酸酯衍生物17b抑制FLT3-ITD的作用至少与TKi AC220（quizartinib）相同。模型表明16和Quizartinib与FLT3有相应的相互作用。16的活性伴随着对FLT3-ITD的高选择性。