Inhibiting Eukaryotic Elongation Factor 2 Kinase: An Update on Pharmacological Small-Molecule Compounds in Cancer

Zhu, Shiou; Liao, Minru; Tan, Huidan; Zhu, Lingjuan; Chen, Yi; He, Gu; Liu, Bo

doi:10.1021/acs.jmedchem.0c02218

Cited by 9 publications

(8 citation statements)

References 69 publications

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“… 281 Fluoxetine was reported to cause autophagic cell death via activating the AMPK-mTOR-ULK1 axis in TNBC cell lines. 282 , 283 Moreover, polyphyllin VI (PPVI) was a natural product with potent antitumor activity, which could regulate multiple pathways to induce autophagic cell death, such as PI3K/Akt/mTOR, MEK/ERK, and AMPK/ mTOR pathways. 284 Apigenin (APG) elicited autophagic cell death by modulating the mTOR-AMPK-ULK1 signaling pathway in GC cell lines.…”

Section: Crucial Signaling Pathways Of Rcd Subroutines In Cancermentioning

confidence: 99%

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Liao

Qin

et al. 2022

Sig Transduct Target Ther

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388

154

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Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.

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Section: Crucial Signaling Pathways Of Rcd Subroutines In Cancermentioning

confidence: 99%

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Liao

Qin

et al. 2022

Sig Transduct Target Ther

Self Cite

388

154

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“…13 C, 1 H-Ile-1, Met-, 2 H, 15 N-labeled CaM (IM-labeled CaM) (41) and unlabeled peEF-2K TR (35) were prepared as previously described, and the corresponding 1:1 heterodimeric complex was purified as described above. All NMR samples (unless specifically noted) were prepared in a buffer (NMR buffer) containing 20 mM Hepes (pH 7.5), 100 mM NaCl, 1.0 mM TCEP, and 5% 2 H 2 O.…”

Section: Solution Nmr Spectroscopymentioning

confidence: 99%

“…Aberrant eEF-2K function has been correlated with enhanced tumorigenesis (12), invasion, and metastasis (13). Given these properties, eEF-2K is an emerging target for the development of therapeutics against several diseases, including many cancers (14)(15)(16), and neuropathies (17), underscoring the importance of understanding its activation and regulation in mechanistic detail.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the calmodulin-mediated activation of eukaryotic elongation factor 2 kinase

et al. 2022

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Translation is a tightly regulated process that ensures optimal protein quality and enables adaptation to energy/nutrient availability. The α-kinase eukaryotic elongation factor 2 kinase (eEF-2K), a key regulator of translation, specifically phosphorylates the guanosine triphosphatase eEF-2, thereby reducing its affinity for the ribosome and suppressing the elongation phase of protein synthesis. eEF-2K activation requires calmodulin binding and autophosphorylation at the primary stimulatory site, T348. Biochemical studies predict a calmodulin-mediated activation mechanism for eEF-2K distinct from other calmodulin-dependent kinases. Here, we resolve the atomic details of this mechanism through a 2.3-Å crystal structure of the heterodimeric complex of calmodulin and the functional core of eEF-2K (eEF-2KTR). This structure, which represents the activated T348-phosphorylated state of eEF-2KTR, highlights an intimate association of the kinase with the calmodulin C-lobe, creating an “activation spine” that connects its amino-terminal calmodulin-targeting motif to its active site through a conserved regulatory element.

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“…Notably, the activity of eEF2K is often found to be enhanced in many types of tumors, and the activated eEF2K in tumor cells is supposed to inhibit protein synthesis, reduces the consumption of nutrients and energy of the cells, thus assisting the tumor cells to resist adverse environments and facilitate their proliferation [ 7 , 8 ]. Consistent with this assumption, a growing number of studies have reported that inhibition of eEF2K expression or activity indeed impairs tumor cells proliferation [ 9 , 10 ]. Therefore, eEF2K is considered as a new potential target for cancer therapy, and the research and development of eEF2K inhibitors are of great clinical significance [ 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 87%

Discovery of New Inhibitors of eEF2K from Traditional Chinese Medicine Based on In Silico Screening and In Vitro Experimental Validation

Liu

et al. 2022

Molecules

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Eukaryotic elongation factor 2 kinase (eEF2K) is a highly conserved α kinase and is increasingly considered as an attractive therapeutic target for cancer as well as other diseases. However, so far, no selective and potent inhibitors of eEF2K have been identified. In this study, pharmacophore screening, homology modeling, and molecular docking methods were adopted to screen novel inhibitor hits of eEF2K from the traditional Chinese medicine database (TCMD), and then cytotoxicity assay and western blotting were performed to verify the validity of the screen. Resultantly, after two steps of screening, a total of 1077 chemicals were obtained as inhibitor hits for eEF2K from all 23,034 compounds in TCMD. Then, to verify the validity, the top 10 purchasable chemicals were further analyzed. Afterward, Oleuropein and Rhoifolin, two reported antitumor chemicals, were found to have low cytotoxicity but potent inhibitory effects on eEF2K activity. Finally, molecular dynamics simulation, pharmacokinetic and toxicological analyses were conducted to evaluate the property and potential of Oleuropein and Rhoifolin to be drugs. Together, by integrating in silico screening and in vitro biochemical studies, Oleuropein and Rhoifolin were revealed as novel eEF2K inhibitors, which will shed new lights for eEF2K-targeting drug development and anticancer therapy.

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Inhibiting Eukaryotic Elongation Factor 2 Kinase: An Update on Pharmacological Small-Molecule Compounds in Cancer

Cited by 9 publications

References 69 publications

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Structural basis for the calmodulin-mediated activation of eukaryotic elongation factor 2 kinase

Discovery of New Inhibitors of eEF2K from Traditional Chinese Medicine Based on In Silico Screening and In Vitro Experimental Validation

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