School of Medicine and Pharmacy, Ocean University of China, and Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
Nutrition & Metabolism, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia.
Eur J Med Chem. 2019 Jan 15;162:735-751. doi: 10.1016/j.ejmech.2018.10.070. Epub 2018 Nov 2.
The mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate eukaryotic initiation factor 4E (eIF4E) and play important roles in promoting tumorigenesis and metabolic disease. Thus, inhibiting these enzymes might be valuable in the treatment of such conditions. We designed and synthesized a series of 4-((4-fluoro-2-isopropoxyphenyl)amino)-5-methylthieno[2,3-d]pyrimidine derivatives, and evaluated their inhibitory activity against the MNKs. We found 15 compounds that were active as MNK inhibitors and that one in particular, designated MNK-7g, which was potent against MNK1 and substantially more potent against MNK2. The compound MNK-7g did not affect other signaling pathways tested and had no adverse effects on cell viability. As expected from earlier studies, MNK-7g also inhibited cell migration. Therefore, the compound MNK-7g, which forms an ionic bond with Asp226 in MNK2 and possesses a substituted aniline in a thieno[2,3-d] pyrimidine structure, is a promising starting point for the future development of novel drugs for treating or managing cancer and metabolic disease.
丝裂原活化蛋白激酶相互作用激酶 1 和 2（MNK1 和 MNK2）磷酸化真核起始因子 4E（eIF4E），并在促进肿瘤发生和代谢性疾病方面发挥重要作用。因此，抑制这些酶在这些疾病的治疗中可能具有重要价值。我们设计并合成了一系列 4-((4-氟-2-异丙氧基苯基)氨基)-5-甲基噻吩并[2,3-d]嘧啶衍生物，并评估了它们对 MNKs 的抑制活性。我们发现了 15 种具有 MNK 抑制活性的化合物，其中一种化合物 MNK-7g 对 MNK1 具有很强的抑制作用，对 MNK2 的抑制作用更强。化合物 MNK-7g 不影响其他测试的信号通路，对细胞活力也没有不良影响。正如早期研究预期的那样，MNK-7g 也抑制细胞迁移。因此，化合物 MNK-7g 与 MNK2 中的 Asp226 形成离子键，并在噻吩并[2,3-d]嘧啶结构中具有取代的苯胺，是未来开发用于治疗或管理癌症和代谢性疾病的新型药物的有前途的起点。
