急性髓系白血病（AML）是一种高度侵袭性的癌症，在成年人中经常被诊断出来，小分子抑制剂已经引起了对AML潜在治疗选择的重要关注。通过生物信息学分析鉴定了AML中的上调基因。通过药理基因组学分析选择潜在的候选药物。进行蛋白质组实验来确定抑制剂治疗后的分子机制。用细胞功能实验和AML小鼠模型评估药物协同作用。通过生物信息学分析，我们筛选出在AML中高表达的基因，从而鉴定出九种小分子抑制剂。在这些抑制剂中，PI3K/mTOR抑制剂VS-5584在低浓度下抑制AML细胞增殖方面显示了显著的有效性。进一步测试显示，VS-5584以剂量和时间依赖的方式诱导了AML细胞的凋亡和周期停滞。蛋白质组学分析显示，在VS-5584处理后，AML细胞的蛋白质表达谱发生了显著变化，其中287种蛋白质被下调，71种蛋白质被上调。GO分析显示，表达差异的蛋白质主要参与调控细胞周期和凋亡。此外，KEGG分析表明，VS-5584的给药主要影响P53和SIRT2信号通路。SIRT2抑制剂SirReal2与VS-5584联合使用在AML细胞上显著降低了半数最大抑制浓度（IC50）。实验证明，VS-5584与SirReal2联合抑制了皮下模型中的肿瘤生长，并延长了经尾静脉注射肿瘤细胞的小鼠的生存率。总的来说，PI3K/mTOR抑制剂VS-5584在抑制AML细胞增殖方面非常有效。PI3K/mTOR抑制剂与SIRT2抑制剂组合在AML细胞中表现出协同抑制作用。我们的研究结果为AML的治疗提供了有希望的治疗策略和候选药物。© 2023 The Authors. Cancer Medicine, 由John Wiley & Sons Ltd.出版。

Acute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML.The up-regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used.Through bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small-molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS-5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS-5584 induced apoptosis and cycle arrest of AML cells in a dose- and time-dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS-5584 treatment, with 287 proteins being down-regulated and 71 proteins being up-regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS-5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS-5584 caused a significant reduction in the half-maximal inhibitory concentration (IC50 ) of VS-5584 on AML cells. In vivo, experiments suggested that VS-5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein.Taken together, the PI3K/mTOR inhibitor VS-5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.