title: Development of DANDYs, new 3,5-diaryl-7-azaindoles demonstrating potent DYRK1A kinase inhibitory activity.
abstract: A series of 3,5-diaryl-1H-pyrrolo[2,3-b]pyridines were synthesized and evaluated for inhibition of DYRKIA kinase in vitro. Derivatives having hydroxy groups on the aryl moieties (2c, 2j-l) demonstrated high inhibitory potencies with Kis in the low nanomolar range. Their methoxy analogues were up to 100 times less active. Docking studies at the ATP binding site suggested that these compounds bind tightly to this site via a network of multiple H-bonds with the peptide backbone. None of the active compounds were cytotoxic to KB cells at 10(-6) M. Kinase profiling revealed that compound 2j showed 2-fold selectivity for DYRK1A with respect to DYRK2 and DYRK3.
authors.affiliation: Institut de Chimie des Substances Naturelles, Centre de Recherche de Gif, UPR 2301, CNRS , Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gourdain
authors.forename: Julien
authors.initials: J
authors.lastname: Dairou
authors.forename: Clément
authors.initials: C
authors.lastname: Denhez
authors.forename: Linh Chi
authors.initials: LC
authors.lastname: Bui
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues-Lima
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
authors.forename: Jean M
authors.initials: JM
authors.lastname: Delabar
authors.forename: Kevin
authors.initials: K
authors.lastname: Cariou
authors.forename: Robert H
authors.initials: RH
authors.lastname: Dodd
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007624:KB Cells; D062105:Molecular Docking Simulation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000097603:Dyrk Kinases
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011725:Pyridines; D000097603:Dyrk Kinases