The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels – TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.

丝裂原激活蛋白激酶（MAPK）相互作用激酶1和2（MNK 1/2）及其下游靶标eIF4E在致癌性转化，进展和转移中发挥作用。这些结果为开发首批MNKs抑制剂提供了理论依据，目前尚在癌症治疗的临床试验中。MNKs / eIF4E途径的抑制剂也被提议作为炎症性疾病的治疗策略。在这里，我们介绍了由吲唑-吡啶酮衍生的MNK1 / 2抑制剂的优化结果，其中包括化合物24和26，选择性和代谢稳定的衍生物。两种化合物均降低了MOLM16细胞系中eIF4E Ser206磷酸化水平（pSer209-eIF4E）的水平。在小鼠体内给药时，化合物24和26在内毒素致死剂量激发模型中，动物的存活率显着提高，同时血清中的促炎细胞因子TNFα和IL-6降低。鉴定出的MNK1 / 2抑制剂代表了一类新型的免疫调节化合物，具有治疗包括败血症在内的炎性疾病的潜力。