title: Design and synthesis of a library of lead-like 2,4-bisheterocyclic substituted thiophenes as selective Dyrk/Clk inhibitors.
abstract: The 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.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: PharmBioTec GmbH, Saarbrücken, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kail
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Marica
authors.initials: M
authors.lastname: Mariano
authors.affiliation: Department of Drug Design and Optimization, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Saarbrücken, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Empting
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Weber
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Paul
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany; Department of Drug Design and Optimization, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000097603:Dyrk Kinases
chemical_list: D053148:Caspase 3; D053179:Caspase 7; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; D013876:Thiophenes; D000097603:Dyrk Kinases; C066780:Clk dual-specificity kinases