Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA.
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Sci Rep. 2017 Jun 30;7(1):4447. doi: 10.1038/s41598-017-04796-1.
Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD AML cells compared to FLT3/ITD cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML.
异常细胞因子信号从突变的受体酪氨酸激酶（RTKs）发起，为高危急性髓性白血病（AML）提供关键的生长和存活信号。FLT3 的抑制剂已经在临床试验中进行了测试，然而，耐药性限制了其临床疗效。突变的受体酪氨酸激酶在 AML 的内质网（ER）中定位异常，并在信号转导和转录激活因子 5（STAT5）的非经典激活中发挥重要作用。在这里，我们测试了一种名为丙咪嗪蓝（IB）的强效新药，它是一种具有双重作用机制的嵌合分子。在 200-300 nM 浓度下，IB 通过抑制 NADPH 氧化酶（NOX）来释放内源性磷酸酶活性，从而成为一种强效的 STAT5 抑制剂。然而，在 75-150 nM 浓度下，IB 通过类似于他普西琼（TG）的机制，通过增加细胞溶质钙，非常有效地杀死突变的 FLT3 驱动的 AML 细胞。IB 还能强烈抑制原代人 FLT3/ITD AML 细胞的存活，而对 FLT3/ITD 细胞无影响，并能保护正常的脐带血细胞。因此，IB 通过一种涉及对失调的钙代谢的易感性的机制起作用，并且融合亲脂性胺到 NOX 抑制染料的组合显示出针对高风险 AML 的进一步临床前开发的前景。
