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

A. Chaikuad , J. Diharce , M. Schröder (1) , Alicia Foucourt (2) , B. Leblond (3) , A.-S. Casagrande (3) , L. Désiré (3) , P. Bonnet (4) , S. Knapp (5) , Thierry Besson (2)

1 AWI - Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung = Alfred Wegener Institute for Polar and Marine Research = Institut Alfred-Wegener pour la recherche polaire et marine
2 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
3 Diaxonhit
4 IP - Institut Pascal
5 UC Davis - University of California [Davis]

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.

Domaines: Chimie

A. Chaikuad, J. Diharce, M. Schröder, Alicia Foucourt, B. Leblond, et al.. 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. Journal of Medicinal Chemistry, 2016, 59 (22), pp.10315-10321. ⟨10.1021/acs.jmedchem.6b01083⟩. ⟨hal-02046195⟩