Using Imidazo[2,1-b][1,3,4]thiadiazol Skeleton to Design and Synthesize Novel MNK Inhibitors,ACS Medicinal Chemistry Letters

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Using Imidazo[2,1-b][1,3,4]thiadiazol Skeleton to Design and Synthesize Novel MNK Inhibitors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-12-15 , DOI: 10.1021/acsmedchemlett.2c00442
Xin Jin _{1,

2,

3} , Tingting Qiu ₁ , Jianling Xie ₂ , Xianfeng Wei ₁ , Xuemin Wang _{2,

4} , Rilei Yu ₁ , Christopher Proud _{2,

4} , Tao Jiang ₁

Affiliation

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：

利用咪唑并[2,1-b][1,3,4]噻二唑骨架设计合成新型MNK抑制剂

丝裂原激活蛋白激酶相互作用蛋白激酶 (MNK) 磷酸化真核起始因子 4E (eIF4E)，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 的活性可以有效治疗癌症。在这项研究中，我们报道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在多种癌细胞系中有效抑制eIF4E的磷酸化。化合物18比MNK1更有效地对抗MNK2，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，阻滞细胞周期。 G0/G1期，并抑制A549细胞的细胞迁移和TNF-α、MCP-1和IL-8的分泌。它代表了设计进一步选择性靶向 MNK 并应用于其他疾病的抑制剂的起始化合物。

更新日期：2022-12-15

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