Excessive eIF4E phosphorylation by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNK1 and MNK2; collectively, MNKs) has been associated with oncogenesis. The overexpression of eIF4E in acute myeloid leukemia (AML) is related to cancer cell growth and survival. Thus, the inhibition of MNKs and eIF4E phosphorylation are potential therapeutic strategies for AML. Herein, a structure-based virtual screening approach was performed to identify potential MNK inhibitors from natural products. Three flavonoids, apigenin, hispidulin, and luteolin, showed MNK2 inhibitory activity with IC₅₀ values of 308, 252, and 579 nM, respectively. A structure–activity relationship analysis was performed to disclose the molecular interactions. Furthermore, luteolin exhibited substantial inhibitory efficacy against MNK1 (IC₅₀ = 179 nM). Experimental results from cellular assays showed that hispidulin and luteolin inhibited the growth of MOLM-13 and MV4-11 AML cells by downregulating eIF4E phosphorylation and arresting the cell cycle at the G0/G1 phase. Therefore, hispidulin and luteolin showed promising results as lead compounds for the potential treatment for AML.

中文翻译：

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选定的黄酮类化合物作为靶向急性髓系白血病的 MNK 抑制剂的生物学评价

丝裂原活化蛋白激酶 (MAPK) 相互作用激酶 1 和 2（MNK1 和 MNK2；统称为 MNK）导致的过度 eIF4E 磷酸化与肿瘤发生有关。eIF4E 在急性髓系白血病 (AML) 中的过表达与癌细胞的生长和存活有关。因此，抑制 MNK 和 eIF4E 磷酸化是 AML 的潜在治疗策略。在此，进行了基于结构的虚拟筛选方法，以从天然产物中识别潜在的 MNK 抑制剂。三种黄酮类化合物，芹菜素、hipidulin 和木犀草素，显示出 MNK2 抑制活性，IC ₅₀值分别为 308、252 和 579 nM。进行构效关系分析以揭示分子相互作用。此外，木犀草素对 MNK1 表现出显着的抑制功效 (IC ₅₀ = 179 nM)。细胞测定的实验结果表明，hipidulin 和木犀草素通过下调 eIF4E 磷酸化和在 G0/G1 期阻止细胞周期来抑制 MOLM-13 和 MV4-11 AML 细胞的生长。因此，hipidulin 和木犀草素作为潜在治疗 AML 的先导化合物显示出有希望的结果。