Fernandez Ann, Monsen Paige J, Platanias Leonidas C, Schiltz Gary E
Department of Chemistry, Northwestern University Evanston IL 60208 USA
Robert H. Lurie Comprehensive Cancer Center Chicago IL 60611 USA.
RSC Med Chem. 2023 May 9;14(6):1060-1087. doi: 10.1039/d3md00121k. eCollection 2023 Jun 22.
Aberrant translation of proteins that promote cell proliferation is an essential factor that defines oncogenic processes and cancer. The process for ribosomal translation of proteins from mRNA requires an essential initiation step which is controlled by the protein eIF4E, which binds the RNA 5'-cap and forms the eIF4F complex that subsequently translates protein. Typically, eIF4E is activated by phosphorylation on Ser209 by MNK1 and MNK2 kinases. Substantial work has shown that eIF4E and MNK1/2 are dysregulated in many cancers and this axis has therefore become an active area of interest for developing new cancer therapeutics. This review summarizes and discusses recent work to develop small molecules that target different steps in the MNK-eIF4E axis as potential cancer therapeutics. The aim of this review is to cover the breadth of different molecular approaches being taken and the medicinal chemistry basis for their optimization and testing as new cancer therapeutics.
促进细胞增殖的蛋白质的异常翻译是定义致癌过程和癌症的一个关键因素。从信使核糖核酸（mRNA）进行核糖体蛋白质翻译的过程需要一个由蛋白质真核生物翻译起始因子4E（eIF4E）控制的关键起始步骤，eIF4E与RNA的5'-帽结合并形成eIF4F复合物，随后该复合物翻译蛋白质。通常，eIF4E通过丝裂原活化蛋白激酶相互作用激酶1（MNK1）和丝裂原活化蛋白激酶相互作用激酶2（MNK2）激酶在丝氨酸209位点的磷酸化而被激活。大量研究表明，eIF4E和MNK1/2在许多癌症中失调，因此该轴已成为开发新型癌症治疗药物的一个活跃研究领域。本综述总结并讨论了最近开发靶向MNK-eIF4E轴不同步骤的小分子作为潜在癌症治疗药物的研究工作。本综述的目的是涵盖所采用的不同分子方法的广度以及将其作为新型癌症治疗药物进行优化和测试的药物化学基础。
