Abstract
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.
Highlights
Down syndrome (DS) is one of the most frequent congenital disorders in humans
The mechanisms leading from trisomy 21 to the clinical disease pattern are not yet understood, the 30 genes located in the so-called Down syndrome critical region (DSCR; 21q22.1−22.3) of chromosome 21 are highly likely to be associated with the disease.[3−5]
There is mounting evidence that overexpression of DYRK1A, a protein kinase encoded by a gene located within DSCR, contributes to mental retardation in DS
Summary
Down syndrome (DS) is one of the most frequent congenital disorders in humans. Individuals with DS exhibit a complex phenotype of structural alterations and intellectual disability. Since DYRK1A is connected to neurological disorders such as AD,[6,7] the early onset of AD in DS individuals has been related to DYRK1A overexpression.[8] Two histopathological features are found in the brains of AD patients: extracellular β-amyloid plaques and intracellular tangles consisting of hyperphosphorylated tau protein.[9] DYRK1A appears to connect these biochemical aberrations.[10] Hyperphosphorylation of tau by DYRK1A diminishes its microtubule-stabilizing effects and increases aggregation.[11] The neurological impairment of mice with modified DYRK1A expression has been attributed to deregulated splicing, leading to an imbalance of 3R-tau and 4Rtau isoforms.[12,13] The increased 3R-tau concentration (by a factor of up to 4) observed in DS has been associated with changes of the neuronal cytoskeleton and neurofibrillary degeneration.[12] DYRK1A-overexpressing mice exhibit increased production of Aβ peptide, which has been attributed to phosphorylation of the amyloid precursor protein (APP) and presenilin 1 by DYRK1A.14,15
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