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The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure-activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site.

Original publication

DOI

10.1021/jm501994d

Type

Journal article

Journal

J Med Chem

Publication Date

09/04/2015

Volume

58

Pages

3131 - 3143

Keywords

Adenosine Triphosphate, Binding Sites, Carboxylic Acids, Chemistry Techniques, Synthetic, Crystallography, X-Ray, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Indoles, Molecular Docking Simulation, Protein Conformation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Quinolones, Structure-Activity Relationship