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10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A
DOI:
10.1021/jm501994d
PMID:
25730262
Authors:
Hannes
Falke
(Technische Universität Braunschweig)
,
Apirat
Chaikuad
(University of Oxford)
,
Anja
Becker
(Technische Universität Braunschweig)
,
Nadã¨ge
Loaec
(Perharidy Research Center)
,
Olivier
Lozach
(CNRS)
,
Samira
Abu Jhaisha
(RWTH Aachen University)
,
Walter
Becker
(RWTH Aachen University)
,
Peter G.
Jones
(Technische Universität Braunschweig)
,
Lutz
Preu
(Technische Universität Braunschweig)
,
Knut
Baumann
(Technische Universität Braunschweig)
,
Stefan
Knapp
(Structural Genomics Consortium, University of Oxford)
,
Laurent
Meijer
(Perharidy Research Center)
,
Conrad
Kunick
(Technische Universität Braunschweig)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Journal Of Medicinal Chemistry
, VOL 58 (7)
State:
Published (Approved)
Published:
March 2015
Diamond Proposal Number(s):
8421
,
10619
Open Access
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 structureactivity 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.
Subject Areas:
Biology and Bio-materials,
Chemistry
Instruments:
I04-1-Macromolecular Crystallography (fixed wavelength)