ArticleChembiochem : a European journal of chemical biology2014
Reversible covalent inhibition of eEF-2K by carbonitriles.
Article in Chembiochem : a European journal of chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 30 citations in OpenAlex.
- Advances in reversible covalent kinase inhibitors.Medicinal research reviews · 2025Review
- Structure of the complex between calmodulin and a functional construct of eukaryotic elongation factor 2 kinase bound to an ATP-competitive inhibitor.The Journal of biological chemistry · 2023Article
- eEF2K Inhibitor Design: The Progression of Exemplary Structure-Based Drug Design.Molecules (Basel, Switzerland) · 2023Review
- Mechanism of reaction of RNA-dependent RNA polymerase from SARS-CoV-2.Chem catalysis · 2022Article
- Structural dynamics of the complex of calmodulin with a minimal functional construct of eukaryotic elongation factor 2 kinase and the role of Thr348 autophosphorylation.Protein science : a publication of the Protein Society · 2021Article
- Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer GrowthACS pharmacology & translational science · 2021Article
- The role of calcium in the interaction between calmodulin and a minimal functional construct of eukaryotic elongation factor 2 kinase.Protein science : a publication of the Protein Society · 2019Article
- Solution Structure of the Carboxy-Terminal Tandem Repeat Domain of Eukaryotic Elongation Factor 2 Kinase and Its Role in Substrate Recognition.Journal of molecular biology · 2019Article
- Structural Dynamics of the Activation of Elongation Factor 2 Kinase by CaJournal of molecular biology · 2018Article
- Structure of the C-Terminal Helical Repeat Domain of Eukaryotic Elongation Factor 2 Kinase.Biochemistry · 2016Article
- Using docking and alchemical free energy approach to determine the binding mechanism of eEF2K inhibitors and prioritizing the compound synthesis.Frontiers in molecular biosciences · 2015Article
- Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors.Bioorganic & medicinal chemistry · 2014Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
eEF-2K is a potential target for treating cancer. However, potent specific inhibitors for this enzyme are lacking. Previously, we identified 2,6-diamino-4-(2-fluorophenyl)-4H-thiopyran-3,5-dicarbonitrile (DFTD) as an inhibitor of eEF-2K. Here we describe its mechanism of action against eEF-2K, on the basis of kinetic, mutational, and docking studies, and use chemoinformatic approaches to identify a similar class of carbonitrile-containing compounds that exhibit the same mechanism of action. We show that DFTD behaves as a reversible covalent inhibitor of eEF-2K with a two-step mechanism of inhibition: a fast initial binding step, followed by a slower reversible inactivation step. Molecular docking suggests that a nitrile group of DFTD binds within 4.5 Å of the active site Cys146 to form a reversible thioimidate adduct. Because Cys146 is not conserved amongst other related kinases, targeting this residue holds promise for the development of selective covalent inhibitors of eEF-2K.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.