Cargando…

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

[Image: see text] 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. H...

Descripción completa

Detalles Bibliográficos
Autores principales: Falke, Hannes, Chaikuad, Apirat, Becker, Anja, Loaëc, Nadège, Lozach, Olivier, Abu Jhaisha, Samira, Becker, Walter, Jones, Peter G., Preu, Lutz, Baumann, Knut, Knapp, Stefan, Meijer, Laurent, Kunick, Conrad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2015
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506206/
https://www.ncbi.nlm.nih.gov/pubmed/25730262
http://dx.doi.org/10.1021/jm501994d
_version_ 1782381661841784832
author Falke, Hannes
Chaikuad, Apirat
Becker, Anja
Loaëc, Nadège
Lozach, Olivier
Abu Jhaisha, Samira
Becker, Walter
Jones, Peter G.
Preu, Lutz
Baumann, Knut
Knapp, Stefan
Meijer, Laurent
Kunick, Conrad
author_facet Falke, Hannes
Chaikuad, Apirat
Becker, Anja
Loaëc, Nadège
Lozach, Olivier
Abu Jhaisha, Samira
Becker, Walter
Jones, Peter G.
Preu, Lutz
Baumann, Knut
Knapp, Stefan
Meijer, Laurent
Kunick, Conrad
author_sort Falke, Hannes
collection PubMed
description [Image: see text] 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.
format Online
Article
Text
id pubmed-4506206
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher American Chemical Society
record_format MEDLINE/PubMed
spelling pubmed-45062062015-07-21 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A Falke, Hannes Chaikuad, Apirat Becker, Anja Loaëc, Nadège Lozach, Olivier Abu Jhaisha, Samira Becker, Walter Jones, Peter G. Preu, Lutz Baumann, Knut Knapp, Stefan Meijer, Laurent Kunick, Conrad J Med Chem [Image: see text] 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. American Chemical Society 2015-03-02 2015-04-09 /pmc/articles/PMC4506206/ /pubmed/25730262 http://dx.doi.org/10.1021/jm501994d Text en Copyright © 2015 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Falke, Hannes
Chaikuad, Apirat
Becker, Anja
Loaëc, Nadège
Lozach, Olivier
Abu Jhaisha, Samira
Becker, Walter
Jones, Peter G.
Preu, Lutz
Baumann, Knut
Knapp, Stefan
Meijer, Laurent
Kunick, Conrad
10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A
title 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A
title_full 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A
title_fullStr 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A
title_full_unstemmed 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A
title_short 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A
title_sort 10-iodo-11h-indolo[3,2-c]quinoline-6-carboxylic acids are selective inhibitors of dyrk1a
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506206/
https://www.ncbi.nlm.nih.gov/pubmed/25730262
http://dx.doi.org/10.1021/jm501994d
work_keys_str_mv AT falkehannes 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT chaikuadapirat 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT beckeranja 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT loaecnadege 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT lozacholivier 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT abujhaishasamira 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT beckerwalter 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT jonespeterg 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT preulutz 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT baumannknut 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT knappstefan 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT meijerlaurent 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a
AT kunickconrad 10iodo11hindolo32cquinoline6carboxylicacidsareselectiveinhibitorsofdyrk1a