Despite progressive advances in understanding the molecular biology of acute myeloid leukemia (AML), the conventional therapeutic approach has not changed substantially, and the outcome for most patients is poor. Thus, continuous efforts on the discovery of new compounds with improved features are required. Following a multistep sequence, we have identified a new tetracyclic ring system with strong antiproliferative activity towards several haematological cell lines. The new compounds possess structural properties typical of inactive-state-binding kinase inhibitors and are structurally related to quizartinib which is known as type-II tyrosine kinase inhibitor. In particular, the high activity found in two cell lines MOLM-13 and MV4-11, expressing the constitutively activated mutant FLT3/ITD, indicates inhibition of FLT3 kinase and on the basis of structure-activity relationship (SAR) the presence of an ureido moiety demonstrates to play a key role in driving the antiproliferative activity towards these cell lines. Molecular modelling studies supported the mechanism of recognition of the most active compounds within the FLT3 pocket where quizartinib binds. Moreover, Molecular Dynamics simulation (MDs) revealed the formation of a recurrent H-bond with Asp829, which more stabilizes the complex of 9c and the FLT3 inactive state.

In MV4-11 cell line compound 9c reduces the phosphorylation of FLT3 (Y591) and some of its downstream targets leading to cell cycle arrest at G1 phase and induction of apoptosis. In an MV4-11 xenograft mouse model, 9c significantly reduces the tumor growth at the dose of 1–3 mg/kg without apparent toxicity.

尽管在了解急性髓性白血病 (AML) 的分子生物学方面取得了进展，但传统的治疗方法并没有发生实质性的变化，并且大多数患者的结果都很差。因此，需要不断努力发现具有改进特征的新化合物。按照多步骤序列，我们已经确定了一种新的四环系统，对几种血液细胞系具有很强的抗增殖活性。新化合物具有非活性状态结合激酶抑制剂的典型结构特性，并且在结构上与被称为 II 型酪氨酸激酶抑制剂的 quizartinib 相关。特别是，在两个细胞系 MOLM-13 和 MV4-11 中发现的高活性，表达组成型激活的突变体 FLT3/ITD，表明 FLT3 激酶的抑制作用，并且基于构效关系 (SAR)，脲基部分的存在证明在驱动对这些细胞系的抗增殖活性中起关键作用。分子模型研究支持识别 quizartinib 结合的 FLT3 口袋中最活跃的化合物的机制。此外，分子动力学模拟 (MDs) 揭示了与 Asp829 形成的循环氢键，这更稳定了图 9c和 FLT3 非活动状态。

在 MV4-11 细胞系中，化合物9c降低了 FLT3 (Y591) 及其一些下游靶标的磷酸化，导致细胞周期停滞在 G1 期并诱导细胞凋亡。在 MV4-11 异种移植小鼠模型中，9c在 1-3 mg/kg 的剂量下显着降低肿瘤生长，而没有明显的毒性。