Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth in Vivo

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dc.authorscopusid55930443900
dc.authorscopusid56711736000
dc.authorscopusid8607330500
dc.authorscopusid6505994829
dc.authorscopusid55326408200
dc.authorscopusid57190610518
dc.authorscopusid56268532500
dc.contributor.authorCömert Önder, F.
dc.contributor.authorKahraman, N.
dc.contributor.authorBellur Atıcı, E.
dc.contributor.authorCagır, A.
dc.contributor.authorKandemir, Hakan
dc.contributor.authorTatar, G.
dc.contributor.authorÖzpolat, Bülent
dc.date.accessioned2022-05-11T14:04:40Z
dc.date.available2022-05-11T14:04:40Z
dc.date.issued2021
dc.departmentFakülteler, Fen Edebiyat Fakültesi, Kimya Bölümü
dc.description.abstractEukaryotic elongation factor 2 kinase (eEF-2K) is an unusual alpha kinase involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is highly overexpressed in breast cancer, and its activity is associated with significantly shortened patient survival and proven to be a potential molecular target in breast cancer. The crystal structure of eEF-2K remains unknown, and there is no potent, safe, and effective inhibitor available for clinical applications. We designed and synthesized several generations of potential inhibitors. The effect of the inhibitors at the binding pocket of eEF-2K was analyzed after developing a 3D target model by using a domain of another ?-kinase called myosin heavy-chain kinase A (MHCKA) that closely resembles eEF-2K. In silico studies showed that compounds with a coumarin-chalcone core have high predicted binding affinities for eEF-2K. Using in vitro studies in highly aggressive and invasive (MDA-MB-436, MDA-MB-231, and BT20) and noninvazive (MCF-7) breast cancer cells, we identified a lead compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and at inhibiting cell proliferation by induction of apoptosis with no toxicity in normal breast epithelial cells. In vivo systemic administration of the lead compound encapsulated in single lipid-based liposomal nanoparticles twice a week significantly suppressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice with no observed toxicity. In conclusion, our study provides a highly potent and in vivo effective novel small-molecule eEF-2K inhibitor that may be used as a molecularly targeted therapy breast cancer or other eEF-2K-dependent tumors. © 2021 American Chemical Society.
dc.description.sponsorship1R01CA244344; University of Texas MD Anderson Cancer Center; Türkiye Bilimsel ve Teknolojik Araştirma Kurumu, TÜBITAK: 215S008, TUBITAK-BIDEB 2214A
dc.description.sponsorshipThis study was funded by The Scientific and Technological Research Council of Turkey (TUBITAK) (grant number 215S008 and TUBITAK-BIDEB 2214A program, F.C.O.) and The University of Texas-MD Anderson Cancer Center Bridge fund (B.O. and N.K.) and NIH-NCI 1R01CA244344 grants (B.O. and N.K.).
dc.identifier.doi10.1021/acsptsci.1c00030
dc.identifier.endpage940
dc.identifier.issn2575-9108
dc.identifier.issue2en_US
dc.identifier.scopus2-s2.0-85105072435
dc.identifier.scopusqualityQ1
dc.identifier.startpage926
dc.identifier.urihttps://doi.org/10.1021/acsptsci.1c00030
dc.identifier.urihttps://hdl.handle.net/20.500.11776/4705
dc.identifier.volume4
dc.identifier.wosWOS:000639067200047
dc.identifier.wosqualityN/A
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.institutionauthorKandemir, Hakan
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.relation.ispartofACS Pharmacology and Translational Science
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectapoptosis
dc.subjectbreast cancer
dc.subjectcoumarin
dc.subjectEF2K
dc.subjectelongation factor 2 kinase
dc.subjectmolecular modeling
dc.subjectchalcone
dc.subjectcoumarin
dc.subjectelongation factor 2 kinase
dc.subjectimidazole derivative
dc.subjectnanoparticle
dc.subjectphosphotransferase inhibitor
dc.subjectprotein kinase B
dc.subjectprotein p53
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectapoptosis
dc.subjectArticle
dc.subjectblood brain barrier
dc.subjectbreast cancer
dc.subjectBT-20 cell line
dc.subjectcancer growth
dc.subjectcancer survival
dc.subjectcardiotoxicity
dc.subjectcell proliferation
dc.subjectcolony formation
dc.subjectcontrolled study
dc.subjectcrystal structure
dc.subjectdensitometry
dc.subjectdrug design
dc.subjectdrug synthesis
dc.subjectenzyme active site
dc.subjectenzyme phosphorylation
dc.subjectfemale
dc.subjectin vitro study
dc.subjectin vivo study
dc.subjectlipophilicity
dc.subjectliposomal delivery
dc.subjectMCF-7 cell line
dc.subjectMDA-MB-231 cell line
dc.subjectMDA-MB-436 cell line
dc.subjectmolecular docking
dc.subjectmolecular dynamics
dc.subjectmolecularly targeted therapy
dc.subjectmouse
dc.subjectnonhuman
dc.subjectpharmacokinetic parameters
dc.subjectpriority journal
dc.subjectquantum mechanics
dc.subjecttime-dependent inhibition
dc.subjecttumor xenograft
dc.subjectWestern blotting
dc.titleTarget-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth in Vivo
dc.typeArticle

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