title: Identification of CLK1 Inhibitors by a Fragment-linking Based Virtual Screening.
abstract: Alternative splicing plays an important role in the regulation of protein biosynthesis. CDC2-like kinases (CLKs) phosphorylate splicing factors rendering them a potential target for treating diseases caused by splicing dysregulation. As selective and potent inhibitors of CLK1 are still lacking, a fragment-linking based virtual screening campaign was successfully applied to identify new inhibitors showing activity on CLK1. These inhibitors exhibit a novel 2,4-substituted 1,3-thiazole scaffold that is suitable for further modification. A subsequently performed docking and protein structure based analysis revealed first hints for inhibitors showing preferred binding activity for CLK1 and DYRK2 over other splicing kinases.
authors.affiliation: Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106, Braunschweig, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Walter
authors.affiliation: Nuffield Department of Clinical Medicine, Chemical Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford, OX3 7DQ, U.K.|Institute of Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe-University Frankfurt, 60438, Frankfurt am Main, Germany.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, 29680, Roscoff, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Loaëc
authors.affiliation: Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106, Braunschweig, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Preu
authors.affiliation: Nuffield Department of Clinical Medicine, Chemical Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford, OX3 7DQ, U.K.|Institute of Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe-University Frankfurt, 60438, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, 29680, Roscoff, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106, Braunschweig, Germany.
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und chemische Biologie, Otto-Hahn-Straße 6, 44227, Dortmund, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Koch
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D062126:Databases, Chemical; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases
keywords: CLK; alternative splicing; scaffold-hopping, fragment-linking; virtual screening