Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Bioorg Med Chem. 2021 Jun 15;40:116186. doi: 10.1016/j.bmc.2021.116186. Epub 2021 May 2.
Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are located at the meeting-point of ERK and p38 MAPK signaling pathways, which can phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at the conserved serine 209 exclusively. MNKs modulate the translation of mRNA involved in tumor-associated signaling pathways. Consequently, selective inhibitors of MNK1/2 could reduce the level of phosphorylated eIF4E. Series of imidazopyrazines, imidazopyridazines and imidazopyridines derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against diffuse large B-cell lymphoma (DLBCL) cell lines. In particular, compound II-5 (MNK1 IC50 = 2.3 nM; MNK2 IC50 = 3.4 nM) exhibited excellent enzymatic inhibitory potency and proved to be the most potent compound against TMD-8 and DOHH-2 cell lines with IC value of 0.3896 μM and 0.4092 μM respectively. These results demonstrated that compound II-5 could be considered as a potential MNK1/2 inhibitor for further investigation.
丝裂原活化蛋白激酶（MAPK）相互作用激酶（MNKs）位于 ERK 和 p38 MAPK 信号通路的交汇点，可特异性地在保守丝氨酸 209 处磷酸化真核翻译起始因子 4E（eIF4E）。MNKs 调节与肿瘤相关信号通路相关的 mRNA 的翻译。因此，MNK1/2 的选择性抑制剂可降低磷酸化 eIF4E 的水平。合成了一系列咪唑并吡嗪、咪唑并哒嗪和咪唑并吡啶衍生物，并将其作为 MNK1/2 抑制剂进行了评估。一些化合物对 MNK1/2 具有很强的抑制活性，一些选定的化合物对弥漫性大 B 细胞淋巴瘤（DLBCL）细胞系表现出中等至优异的抗增殖活性。特别是化合物 II-5（MNK1 IC50=2.3 nM；MNK2 IC50=3.4 nM）表现出优异的酶抑制活性，并被证明对 TMD-8 和 DOHH-2 细胞系具有最强的活性，IC 值分别为 0.3896 μM 和 0.4092 μM。这些结果表明，化合物 II-5 可被视为进一步研究的潜在 MNK1/2 抑制剂。
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