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dc.contributor.authorSchmitt, Christian
dc.contributor.authorKail, Dagmar
dc.contributor.authorMariano, Marica
dc.contributor.authorEmpting, Martin
dc.contributor.authorWeber, Nadja
dc.contributor.authorPaul, Tamara
dc.contributor.authorHartmann, Rolf W.
dc.contributor.authorEngel, Matthias
dc.date.accessioned2017-07-25T13:56:49Z
dc.date.available2017-07-25T13:56:49Z
dc.date.issued2014
dc.identifier.citationDesign and synthesis of a library of lead-like 2,4-bisheterocyclic substituted thiophenes as selective Dyrk/Clk inhibitors. 2014, 9 (3):e87851 PLoS ONEen
dc.identifier.issn1932-6203
dc.identifier.pmid24676346
dc.identifier.doi10.1371/journal.pone.0087851
dc.identifier.urihttp://hdl.handle.net/10033/621019
dc.description.abstractThe Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform-mediated functions.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshCaspase 3en
dc.subject.meshCaspase 7en
dc.subject.meshCell Line, Tumoren
dc.subject.meshCricetinaeen
dc.subject.meshDrug Designen
dc.subject.meshDrug Evaluation, Preclinicalen
dc.subject.meshDrug Screening Assays, Antitumoren
dc.subject.meshGene Expression Regulationen
dc.subject.meshHumansen
dc.subject.meshInhibitory Concentration 50en
dc.subject.meshModels, Molecularen
dc.subject.meshMolecular Conformationen
dc.subject.meshMolecular Structureen
dc.subject.meshProtein Kinase Inhibitorsen
dc.subject.meshProtein-Serine-Threonine Kinasesen
dc.subject.meshProtein-Tyrosine Kinasesen
dc.subject.meshReactive Oxygen Speciesen
dc.subject.meshRecombinant Fusion Proteinsen
dc.subject.meshSmall Molecule Librariesen
dc.subject.meshStructure-Activity Relationshipen
dc.subject.meshThiophenesen
dc.titleDesign and synthesis of a library of lead-like 2,4-bisheterocyclic substituted thiophenes as selective Dyrk/Clk inhibitors.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Institute für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.en
dc.identifier.journalPloS oneen
refterms.dateFOA2018-06-12T17:23:07Z
html.description.abstractThe Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform-mediated functions.


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