Eef2k: an Atypical Kinase Target for Cancer
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NEWS & ANALYSIS BIOBUSINESS BRIEFS TARGET WATCH hyperphosphorylation and improved memory deficits in mouse models of AD eEF2K: an atypical kinase (J. Clin. Invest. 129, 820–833; 2019). Chemical tools Although eEF2K is not inhibited by some target for cancer of the most prolific kinase inhibitors such as staurosporine, and no complete protein Eukaryotic elongation factor 2 kinase (eEF2K) which is involved in glutamine homeostasis crystal structure is available, there are some is an atypical member of the α-kinase family, and AMPK regulation, was also identified as compounds that have been reported as eEF2K and shows no sequence similarity to classical a substrate (J. Mol. Med. 98, 775–787; 2020). inhibitors (J. Mol. Med. 98, 775–787; 2020). protein kinases. The identification of eEF2K Overexpression of eEF2K has been One of the earliest reported inhibitors as a key regulator of several cellular processes correlated with low survival rates in patients of eEF2K is an imidazole compound implicated in tumorigenesis, as well as reports with various solid tumours, including brain, known as NH125. However, although this of its upregulation in various cancers and esophageal, pancreatic, lung and triple-negative compound inhibits the enzyme in vitro linkage to poor patient outcomes, has led to breast cancer. The inhibition of eEF2K has (IC50 = 0.060 μM) and has potent anticancer growing interest in its potential as an anticancer been linked to apoptotic and autophagic cancer activity, it was found that it actually induces target (J. Mol. Med. 98, 775–787; 2020). cell death, as well as decreased VEGF levels eEF2 phosphorylation in cells, and competes and angiogenesis (J. Mol. Med. 98, 775–787; with calmodulin rather than ATP as a Biological functions 2020). In addition, the inhibition of eEF2K mechanism of action (J. Biol. Chem. 286, eEF2K was reported in the late 1980s as a has recently been shown to synergise with 43951–43858; 2011). Consequently, it is not structurally and functionally unique protein glutaminase inhibitors or 4EBP1 depletion in a suitable tool for investigating the anticancer kinase involved in calmodulin-mediated the suppression of triple-negative breast cancer potential of inhibiting eEF2K. In the same signalling pathways. Its substrate, eEF2, cell growth (Sci. Rep. 11, 9181; 2021). study, the identification of a selective but helps ribosomes proceed with mRNAs during As well as cancer, eEF2K has been weak inhibitor of eEF2K (IC50 = 0.28 μM) the elongation step of protein synthesis. implicated in several neurological diseases. called A-484954 through a high-throughput Phosphorylation of eEF2 on its highly For example, abnormal hyperphosphorylation screen was also reported (FIG. 1b). A-484954 conserved Thr56 residue inhibits its activity of eEF2 has been observed in post-mortem decreased eEF2 phosphorylation in cells, but and thereby negatively regulates protein brain tissue from patients with Alzheimer had little effect on cancer cell growth. synthesis (FIG. 1a). More recently, the α4 disease (AD), and genetic reduction of So far, no selective and suitably potent regulatory subunit of phosphatase 2A (PP2A), eEF2K suppressed AD-associated eEF2 inhibitors of eEF2K have been identified, and such compounds are needed to better a • Hormones Glutamate Low energy understand the potential of eEF2K as a • Growth factors status target for cancer, as well as other diseases. • Amino acids Concomitant inhibition of proteins that cooperate with eEF2K in maintaining proteostasis such as HSP90 (J. Biol. Chem. mTORC1 MEK/ERK mTORC1/S6K1 NMDAR AMPK 294, 7169–7176; 2019) could also be a promising anticancer strategy. Louisa Temme1,3 ✉ and Christopher R. M. Asquith2,3 ✉ Ca2+ influx 1Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Münster, Germany. 2Department of Pharmacology, School of Medicine, Calmodulin University of North Carolina at Chapel Hill, NC, USA. MAPK 3These authors contributed equally: Louisa Temme, Christopher R. M. Asquith. PKA ✉e-mail: [email protected]; [email protected] eEF2K https://doi.org/10.1038/d41573-021-00124-5 b GSK3 Acknowledgements O O This article is part of a series from the NIH Common Fund Illuminating the Druggable Genome (IDG) program. The goal of IDG is to catalyse research on understudied N NH 2 mGluR proteins from druggable gene families by providing eEF2 eEF2 P reagents, phenotypes and a mineable database; focusing on O N N NH2 Thr56 GPCRs, kinases and ion channels. For more information, see https://druggablegenome.net/ Active Inactive Competing interests A-484954 ↑ Translation ↓ Translation The authors declare no competing interests. eEF2K IC50 = 0.28 μM elongation elongation RELATED LINKS Fig. 1 | eEF2K as an anticancer drug target. a | eEF2K signalling pathway and partners. In cancer Pharos (EEF2K): https://pharos.nih.gov/targets/eef2k cells, eEF2K activity can support cell survival in the face of nutrient deprivation by suppressing Dark Kinase Knowledgebase (EEF2K): https://darkkinome.org/ translation elongation. b | Structure of A-484954, a selective eEF2K inhibitor. kinase/EEF2K NATURE REVIEWS | DRUG DISCOVERY VOLUME 20 | AUGUST 2021 | 577 0123456789();: .