title: An Unusual Binding Model of the Methyl 9-Anilinothiazolo[5,4-f] quinazoline-2-carbimidates (EHT 1610 and EHT 5372) Confers High Selectivity for Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases.
abstract: Methyl 9-anilinothiazolo[5,4-f]quinazoline-2-carbimidates 1 (EHT 5372) and 2 (EHT 1610) are strong inhibitors of DYRK's family kinases. The crystal structures of the complex revealed a noncanonical binding mode of compounds 1 and 2 in DYRK2, explaining the remarkable selectivity and potency of these inhibitors. The structural data and comparison presented here provide therefore a template for further improvement of this inhibitor class and for the development of novel inhibitors selectively targeting DYRK kinases.
authors: Target Discovery Institute (TDI), and Structural Genomics Consortium (SGC), University of Oxford , Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
authors: Apirat
authors: A
authors: Chaikuad
authors: Institut de Chimie Organique et Analytique, UMR CNRS-Université d'Orléans 7311, Université d'Orléans , BP 6759, Orléans 45067 Cedex 2, France.
authors: Julien
authors: J
authors: Diharce
authors: Institute of Pharmaceutical Chemistry and Buchman Institute for Life Sciences, Goethe-University , Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
authors: Martin
authors: M
authors: Schröder
authors: Normandie Univ, UNIROUEN, INSA Rouen, CNRS , COBRA UMR 6014, 76000 Rouen, France.
authors: Alicia
authors: A
authors: Foucourt
authors: Diaxonhit , 63-65 Boulevard Masséna, 75013 Paris, France.
authors: Bertrand
authors: B
authors: Leblond
authors: Diaxonhit , 63-65 Boulevard Masséna, 75013 Paris, France.
authors: Anne-Sophie
authors: AS
authors: Casagrande
authors: Diaxonhit , 63-65 Boulevard Masséna, 75013 Paris, France.
authors: Laurent
authors: L
authors: Désiré
authors: Institut de Chimie Organique et Analytique, UMR CNRS-Université d'Orléans 7311, Université d'Orléans , BP 6759, Orléans 45067 Cedex 2, France.
authors: Pascal
authors: P
authors: Bonnet
authors: Target Discovery Institute (TDI), and Structural Genomics Consortium (SGC), University of Oxford , Old Road Campus Research Building, Oxford OX3 7DQ, U.K.|Institute of Pharmaceutical Chemistry and Buchman Institute for Life Sciences, Goethe-University , Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
authors: Stefan
authors: S
authors: Knapp
authors: Normandie Univ, UNIROUEN, INSA Rouen, CNRS , COBRA UMR 6014, 76000 Rouen, France.
authors: Thierry
authors: T
authors: Besson
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000620278:EHT 1610; C000620281:EHT 5372; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases