Mitogen-activated protein kinase-interacting protein kinases (MNKs) phosphorylate eukaryotic initiation factor 4E (eIF4E) and regulate the processes of cell proliferation, cell cycle, and migration and invasion of cancer cells. Selectively inhibiting the activity of MNKs could be effective in treating cancers. In this study, we report a series of novel MNK inhibitors with an imidazo[2,1-b][1,3,4]thiadiazol scaffold, from which, compound 18 inhibited the phosphorylation of eIF4E in various cancer cell lines potently. Compound 18 was more potent against MNK2 than MNK1, and decreased the levels of cyclin-B1, cyclin-D3, and MMP-3 in A549 and MDA-MB-231 cells, impaired cell growth and colony formation, arrested the cell cycle in the G0/G1 phase, and inhibited cell migration and the secretion of TNF-α, MCP-1, and IL-8 from A549 cells. It represents a starting compound to design further inhibitors that selectively target MNKs and apply in other diseases.

中文翻译：

---

利用咪唑[2,1-b][1,3,4]噻二唑骨架设计合成新型MNK抑制剂

丝裂原活化蛋白激酶相互作用蛋白激酶 (MNK) 磷酸化真核起始因子 4E (eIF4E) 并调节细胞增殖、细胞周期以及癌细胞的迁移和侵袭过程。选择性抑制 MNK 的活性可有效治疗癌症。在这项研究中，我们报告了一系列具有咪唑并 [2,1- b ][1,3,4] 噻二唑支架的新型 MNK 抑制剂，其中化合物18可有效抑制各种癌细胞系中 eIF4E 的磷酸化。化合物18比 MNK1 对 MNK2 更有效，并降低 A549 和 MDA-MB-231 细胞中细胞周期蛋白-B1、细胞周期蛋白-D3 和 MMP-3 的水平，损害细胞生长和集落形成，使细胞周期停滞在 G0/ G1期，抑制A549细胞的细胞迁移和TNF-α、MCP-1、IL-8的分泌。它代表了一种起始化合物，可用于设计更多选择性靶向 MNK 并应用于其他疾病的抑制剂。