Abstract
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.
Highlights
Targeted therapy is an important strategy for cancer treatment, and this has been well applied in actual clinical applications [1]
Increasing evidence shows that Eukaryotic elongation factor 2 kinase (eEF2K) is highly expressed in a variety of tumor tissues and that it is related to the development and prognosis of several kinds of malignancies such as breast cancer, ovarian cancer, colon cancer, glioma, medulloblastoma, hepatocellular carcinoma, and prostate cancer [7,8,9,10,11,12]
What is known about the structure of eEF2K and the specific regulation of the extension process has been reviewed in detail by Proud [5], as well as more recently by Karakas and Ozpolat [13], and will not be elaborated here
Summary
Targeted therapy is an important strategy for cancer treatment, and this has been well applied in actual clinical applications [1]. Most clinically used targeted cancer drugs are inhibitors of tyrosine kinases [1,2]. Even when these drugs have exceptional efficacy initially, the later emergence of drug resistance limits their usefulness [2]. EEF2K can participate in the regulation of the tumor cell cycle, proliferation, autophagy, apoptosis, angiogenesis, invasion, and metastasis, among other processes [13,14,15]. For all of these reasons, eEF2K is a potential therapeutic target for anticancer drug development. A summary of recent research progress on eEF2K inhibitors for cancer chemotherapy is presented along with the detailed structure–activity relationships (SARs) and synthetic routes or natural sources of existing eEF2K inhibitors
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