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Design, Synthesis, and Molecular Modeling Studies of Novel Coumarin Carboxamide Derivatives as eEF-2K Inhibitors
journal contribution
posted on 2020-02-20, 19:45 authored by Ferah Comert Onder, Serdar Durdagi, Kader Sahin, Bulent Ozpolat, Mehmet AyEukaryotic
elongation factor-2 kinase (eEF-2K) is an unusual alpha
kinase commonly upregulated in various human cancers, including breast,
pancreatic, lung, and brain tumors. We have demonstrated that eEF-2K
is relevant to poor prognosis and shorter patient survival in breast
and lung cancers and validated it as a molecular target using genetic
methods in related in vivo tumor models. Although
several eEF-2K inhibitors have been published, none of them have shown
to be potent and specific enough for translation into clinical trials.
Therefore, development of highly effective novel inhibitors targeting
eEF-2K is needed for clinical applications. However, currently, the
crystal structure of eEF-2K is not known, limiting the efforts for
designing novel inhibitor compounds. Therefore, using homology modeling
of eEF-2K, we designed and synthesized novel coumarin-3-carboxamides
including compounds A1, A2, and B1–B4 and evaluated their activity by performing in silico analysis and in vitro biological assays in breast
cancer cells. The Molecular Mechanics/Generalized Born Surface Area
(MM/GBSA) area results showed that A1 and A2 have interaction energies with eEF-2K better than those of B1–B4 compounds. Our in vitro results indicated that compounds A1 and A2 were highly effective in inhibiting eEF-2K at 1.0 and 2.5 μM
concentrations compared to compounds B1–B4, supporting
the in silico findings. In conclusion, the results
of this study suggest that our homology modeling along with in silico analysis may be effectively used to design inhibitors
for eEF-2K. Our newly synthesized compounds A1 and A2 may be used as novel eEF-2K inhibitors with potential therapeutic
applications.
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vivo tumor modelshomology modelingeEF -2Knovel inhibitor compoundsNovel Coumarin Carboxamide Derivativesnovel coumarin -3-carboxamidesMMbreast cancer cellseEF -2K inhibitorssilico analysis2.5 μ M concentrationsMolecular Modeling Studiesnovel eEF -2K inhibitorseEF -2K Inhibitors Eukaryotic elongation factor -2 kinase
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