Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo 315800, China.
Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China.
Int J Mol Sci. 2021 Feb 27;22(5):2408. doi: 10.3390/ijms22052408.
Eukaryotic elongation factor 2 kinase (eEF2K or Ca2+/calmodulin-dependent protein kinase, CAMKIII) is a new member of an atypical α-kinase family different from conventional protein kinases that is now considered as a potential target for the treatment of cancer. This protein regulates the phosphorylation of eukaryotic elongation factor 2 (eEF2) to restrain activity and inhibit the elongation stage of protein synthesis. Mounting evidence shows that eEF2K regulates the cell cycle, autophagy, apoptosis, angiogenesis, invasion, and metastasis in several types of cancers. The expression of eEF2K promotes survival of cancer cells, and the level of this protein is increased in many cancer cells to adapt them to the microenvironment conditions including hypoxia, nutrient depletion, and acidosis. The physiological function of eEF2K and its role in the development and progression of cancer are here reviewed in detail. In addition, a summary of progress for in vitro eEF2K inhibitors from anti-cancer drug discovery research in recent years, along with their structure-activity relationships (SARs) and synthetic routes or natural sources, is also described. Special attention is given to those inhibitors that have been already validated in vivo with the overall aim to provide reference context for the further development of new first-in-class anti-cancer drugs that target eEF2K.
真核延伸因子 2 激酶（eEF2K 或钙/钙调蛋白依赖性蛋白激酶，CAMKIII）是一种新型的非典型 α-激酶家族成员，与传统蛋白激酶不同，它现在被认为是癌症治疗的潜在靶点。这种蛋白调节真核延伸因子 2（eEF2）的磷酸化，从而抑制其活性并抑制蛋白质合成的延伸阶段。越来越多的证据表明，eEF2K 调节多种类型癌症中的细胞周期、自噬、细胞凋亡、血管生成、侵袭和转移。eEF2K 的表达促进了癌细胞的存活，并且许多癌细胞中这种蛋白的水平增加，以适应包括缺氧、营养耗竭和酸中毒在内的微环境条件。本文详细综述了 eEF2K 的生理功能及其在癌症发生和发展中的作用。此外，还概述了近年来抗癌药物发现研究中体外 eEF2K 抑制剂的进展情况，包括其构效关系（SAR）和合成路线或天然来源。特别关注那些已经在体内得到验证的抑制剂，以期为靶向 eEF2K 的新型首创抗癌药物的进一步开发提供参考背景。
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