Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD+ induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 inhibitors and investigated 5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7; 7c) as candidates for the treatment of AML. The results showed that 7c inhibited the activities of FLT3 and mutated FLT3 in a cell-free kinase assay and Molm-13 and MV4-11 cells, as well as the proliferation of FLT3-ITD+ AML cells, increasing apoptosis. The anti-leukemic activity of 7c was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, 7c suppressed the expression of DNA damage repair genes. Combination treatment with 7c and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that 7c is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with 7c and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.

中文翻译：

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发现恶唑-2-胺衍生物作为有效的新型 FLT3 抑制剂

FMS 样酪氨酸激酶 3 (FLT3) 的内部串联重复 (ITD) 是急性髓系白血病 (AML) 患者中最常见的突变。FLT3-ITD+ 诱导 FLT3 的组成型激活，导致癌细胞异常快速增殖。在这项研究中，我们确定了新型 FLT3 抑制剂并研究了 5-(4-氟苯基)-N-苯基恶唑-2-胺（化合物 7；7c）作为治疗 AML 的候选药物。结果表明，7c 在无细胞激酶测定中抑制 FLT3 和突变的 FLT3 以及 Molm-13 和 MV4-11 细胞的活性，以及​​ FLT3-ITD+ AML 细胞的增殖，增加细胞凋亡。7c 的抗白血病活性通过 MV4-11 异种移植小鼠体内肿瘤生长抑制得到证实。此外，7c抑制DNA损伤修复基因的表达。用 7c 和 olaparib（一种聚（ADP-核糖）聚合酶 [PARP] 抑制剂）联合治疗可协同抑制 Molm-13 和 MV4-11 细胞的细胞增殖。我们的研究结果表明，7c 是一种靶向 FLT3 用于 AML 治疗的候选药物，并表明 7c 和 PARP 抑制剂的联合治疗可能是 FLT3 突变的 AML 的有效治疗方案。