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, 58 (7), 3131-43

10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A


10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A

Hannes Falke et al. J Med Chem.


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.


Chart 1
Chart 1. Three Reported DYRK1A Inhibitors
Scheme 1
Scheme 1. Synthesis of 11H-Indolo[3,2-c]quinoline-6-carboxylic Acids 5 by Rearrangement of Paullones 4
Reagents and conditions: Co(II) acetate, NHPI, air or O2, DMF, room temperature to 70 °C (13–88%).
Scheme 2
Scheme 2. Synthesis of Paullones 4
Reagents and conditions: (i) (1) AcOH, NaOAc, 70 °C, (2) AcOH, H2SO4, 70 °C. For residues R1–R4 refer to Tables 1 and 2.
Scheme 3
Scheme 3. Synthesis of Ethyl 11H-Indolo[3,2-c]quinoline-6-carboxylates 10
For substitution pattern, refer to Table 2. Reagents and conditions: (i) EtOH, HCl (g), room temperature, 30 min (27–75%).
Figure 1
Figure 1
Crystal structure of the ethyl ester 10o as its monohydrate.
Figure 2
Figure 2
Efficacy of compound 5j in cell-based assays. (A) HeLa cells expressing GFP-SF3B1 were treated with compound 5j or the reference inhibitor leucettine 41 (L41) as indicated. Phosphorylation of SF3B1 was determined by immunoblotting with a pThr434 antibody, and expression levels of GFP-SF3B1 were assessed with GFP antibody. The left panel shows Western blots of a representative experiment, and the graph presents the quantitative evaluation of three experiments as the mean values of normalized pThr434 immunoreactivity relative to that in untreated cells ± SEM. (B) Stably transfected HEK293-tau-DYRK1A cells were treated with doxycyclin (except lane 1, Ctrl) to induce the expression of GFP-DYRK1A and compound 5j or the reference inhibitor leucettine 41 (L41). Phosphorylation of tau on Thr212 (pT212) was detected by immunoblotting with a phosphospecific antibody, and expression levels of the recombinant proteins were determined with a GFP antibody. To correct for basal tau phosphorylation not caused by DYRK1A, the pT212 immunoreactivity in L41 treated cells was subtracted as background. The graph presents the results of three experiments as the mean values of pThr212 immunoreactivity relative to that in untreated cells ± SEM. Curve fitting yielded IC50 = 0.5 μM (95% confidence interval 0.3–0.8 μM) for the inhibition of SF3B1 phosphorylation and IC50 = 2.1 μM (95% confidence interval 1.2–3.6 μM) for the inhibition of tau phosphorylation.
Figure 3
Figure 3
Representative orientations of the 10 highest-ranked docking poses of 5i in the ATP binding site of DYRK1A (template for docking, 2WO6): (a) ranks in the scoring list, 1–3; (b) ranks in the scoring list, 4 and 7; (c) ranks in the scoring list, 5, 6, 10; (d) ranks in the scoring list, 8, 9. P.1 refers to the pose ranked no. 1.
Figure 4
Figure 4
Crystal structure analyses of the binding modes of halogen-substituted DYRK1A inhibitors. Accommodations of three halogen derivatives comprising iodo (5j, A), chloro (5s, B), and bromo (5t, C) substitutions at the position 10 within the ATP pocket share common features of hydrogen bond network interactions (yellow dashed lines) with the kinase. Insets show electron density maps for the bound inhibitors, and water molecules are shown in cyan spheres. (D) Detailed distances and C–X···O angles (putative σ-hole angles) between the halogen groups of the inhibitors and the carbonyl atom of gk + 3 Leu241.

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