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

  • J Med Chem. 2016 Nov 23;59(22):10315-10321. doi: 10.1021/acs.jmedchem.6b01083.
Apirat Chaikuad  1 ,  Julien Diharce  2 ,  Martin Schröder  3 ,  Alicia Foucourt  4 ,  Bertrand Leblond  5 ,  Anne-Sophie Casagrande  5 ,  Laurent Désiré  5 ,  Pascal Bonnet  2 ,  Stefan Knapp  1  3 ,  Thierry Besson  4
Affiliations
  • 1. Target Discovery Institute (TDI), and Structural Genomics Consortium (SGC), University of Oxford , Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
  • 2. Institut de Chimie Organique et Analytique, UMR CNRS-Université d'Orléans 7311, Université d'Orléans , BP 6759, Orléans 45067 Cedex 2, France.
  • 3. Institute of Pharmaceutical Chemistry and Buchman Institute for Life Sciences, Goethe-University , Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
  • 4. Normandie Univ, UNIROUEN, INSA Rouen, CNRS , COBRA UMR 6014, 76000 Rouen, France.
  • 5. Diaxonhit , 63-65 Boulevard Masséna, 75013 Paris, France.
PMID: 27766861 DOI: 10.1021/acs.jmedchem.6b01083
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.

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