The protein kinase DYRK1A has beensuggested to act as one of theintracellular regulators contributing to neurological alterationsfound in individuals with Down syndrome. For an assessment of therole of DYRK1A, selective synthetic inhibitors are valuable pharmacologicaltools. However, the DYRK1A inhibitors described in the literatureso far either are not sufficiently selective or have not been testedagainst closely related kinases from the DYRK and the CLK proteinkinase families. The aim of this study was the identification of DYRK1Ainhibitors exhibiting selectivity versus the structurally and functionallyclosely related DYRK and CLK isoforms. Structure modification of thescreening hit 11H-indolo[3,2-c]quinoline-6-carboxylicacid revealed structure–activity relationships for kinase inhibitionand enabled the design of 10-iodo-substituted derivatives as verypotent DYRK1A inhibitors with considerable selectivity against CLKs.X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1Aconfirmed the predicted binding mode within the ATP binding site. [ABSTRACT FROM AUTHOR]