FMS-like tyrosine receptor kinase 3 (FLT3) mutations, the most common genetic alterations found in acute myeloid leukemia (AML) patients, have been pursued as an ideal drug discovery target for the AML therapy. Taking compound 2 as lead, a series of pyridine derivatives bearing 1,2,3-triazole moiety were rationally designed and synthesized. The bioassays confirmed that these derivatives exerted potent antileukemia effects, and compound 12y was found to be the most potent one. 12y displayed double-digital nanomolar inhibitory activities against FLT3-ITD and FLT3-ITD driven human AML MOLM-13 cells as well as high selectivity over FLT3-ITD non-addicted cell lines. In addition, kinase profiling versus over 51 kinases demonstrated that 12y was potent against FLT3-ITD and VEGFR2. Moreover, treatment of MOLM-13 cells with 12y resulted in downregulated phosphorylation levels of FLT3 and STAT5, as well as cell cycle arrest and apoptosis. With the acceptable oral bioavailability of 19.2 % in SD rats, 12y prolonged the survival rate of NSG mice dose-dependently in MOLM-13 inoculated xenograft model without obvious toxicity. Overall, this study might provide a new insight for the development of novel FLT3 inhibitors.

中文翻译：

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发现基于吡啶的衍生物作为 FLT3 抑制剂治疗急性髓性白血病


FMS 样酪氨酸受体激酶 3 （FLT3） 突变是急性髓性白血病 （AML） 患者中最常见的基因改变，已被作为 AML 治疗的理想药物发现靶点。以化合物 2 为铅，合理设计合成了一系列带有 1,2,3-三唑部分的吡啶衍生物。生物测定证实这些衍生物发挥了强大的抗白血病作用，发现化合物 12y 是最有效的一种。12y 对 FLT3-ITD 和 FLT3-ITD 驱动的人 AML MOLM-13 细胞显示出双数字纳摩尔抑制活性，并且对 FLT3-ITD 非成瘾细胞系具有高选择性。此外，与超过 51 种激酶的激酶分析表明，12y 对 FLT3-ITD 和 VEGFR2 有效。此外，用 12 年处理 MOLM-13 细胞导致 FLT3 和 STAT5 的磷酸化水平下调，以及细胞周期停滞和细胞凋亡。SD 大鼠可接受的口服生物利用度为 19.2%，在 MOLM-13 接种的异种移植模型中，12y 剂量依赖性地延长了 NSG 小鼠的存活率，没有明显的毒性。总的来说，这项研究可能为新型 FLT3 抑制剂的开发提供新的见解。