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Identification and Characterization of Amlexanox as a G Protein-Coupled Receptor Kinase 5 Inhibitor

G protein-coupled receptor kinases (GRKs) have been implicated in human diseases ranging from heart failure to diabetes. Previous studies have identified several compounds that selectively inhibit GRK2, such as paroxetine and balanol. Far fewer selective inhibitors have been reported for GRK5, a tar...

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Autores principales: Homan, Kristoff T., Wu, Emily, Cannavo, Alessandro, Koch, Walter J., Tesmer, John J. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621012/
https://www.ncbi.nlm.nih.gov/pubmed/25340299
http://dx.doi.org/10.3390/molecules191016937
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author Homan, Kristoff T.
Wu, Emily
Cannavo, Alessandro
Koch, Walter J.
Tesmer, John J. G.
author_facet Homan, Kristoff T.
Wu, Emily
Cannavo, Alessandro
Koch, Walter J.
Tesmer, John J. G.
author_sort Homan, Kristoff T.
collection PubMed
description G protein-coupled receptor kinases (GRKs) have been implicated in human diseases ranging from heart failure to diabetes. Previous studies have identified several compounds that selectively inhibit GRK2, such as paroxetine and balanol. Far fewer selective inhibitors have been reported for GRK5, a target for the treatment of cardiac hypertrophy, and the mechanism of action of reported compounds is unknown. To identify novel scaffolds that selectively inhibit GRK5, a differential scanning fluorometry screen was used to probe a library of 4480 compounds. The best hit was amlexanox, an FDA-approved anti-inflammatory, anti-allergic immunomodulator. The crystal structure of amlexanox in complex with GRK1 demonstrates that its tricyclic aromatic ring system forms ATP-like interactions with the hinge of the kinase domain, which is likely similar to how this drug binds to IκB kinase ε (IKKε), another kinase known to be inhibited by this compound. Amlexanox was also able to inhibit myocyte enhancer factor 2 transcriptional activity in neonatal rat ventricular myocytes in a manner consistent with GRK5 inhibition. The GRK1 amlexanox structure thus serves as a springboard for the rational design of inhibitors with improved potency and selectivity for GRK5 and IKKε.
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spelling pubmed-46210122015-10-26 Identification and Characterization of Amlexanox as a G Protein-Coupled Receptor Kinase 5 Inhibitor Homan, Kristoff T. Wu, Emily Cannavo, Alessandro Koch, Walter J. Tesmer, John J. G. Molecules Article G protein-coupled receptor kinases (GRKs) have been implicated in human diseases ranging from heart failure to diabetes. Previous studies have identified several compounds that selectively inhibit GRK2, such as paroxetine and balanol. Far fewer selective inhibitors have been reported for GRK5, a target for the treatment of cardiac hypertrophy, and the mechanism of action of reported compounds is unknown. To identify novel scaffolds that selectively inhibit GRK5, a differential scanning fluorometry screen was used to probe a library of 4480 compounds. The best hit was amlexanox, an FDA-approved anti-inflammatory, anti-allergic immunomodulator. The crystal structure of amlexanox in complex with GRK1 demonstrates that its tricyclic aromatic ring system forms ATP-like interactions with the hinge of the kinase domain, which is likely similar to how this drug binds to IκB kinase ε (IKKε), another kinase known to be inhibited by this compound. Amlexanox was also able to inhibit myocyte enhancer factor 2 transcriptional activity in neonatal rat ventricular myocytes in a manner consistent with GRK5 inhibition. The GRK1 amlexanox structure thus serves as a springboard for the rational design of inhibitors with improved potency and selectivity for GRK5 and IKKε. MDPI 2014-10-22 /pmc/articles/PMC4621012/ /pubmed/25340299 http://dx.doi.org/10.3390/molecules191016937 Text en © 2014 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Homan, Kristoff T.
Wu, Emily
Cannavo, Alessandro
Koch, Walter J.
Tesmer, John J. G.
Identification and Characterization of Amlexanox as a G Protein-Coupled Receptor Kinase 5 Inhibitor
title Identification and Characterization of Amlexanox as a G Protein-Coupled Receptor Kinase 5 Inhibitor
title_full Identification and Characterization of Amlexanox as a G Protein-Coupled Receptor Kinase 5 Inhibitor
title_fullStr Identification and Characterization of Amlexanox as a G Protein-Coupled Receptor Kinase 5 Inhibitor
title_full_unstemmed Identification and Characterization of Amlexanox as a G Protein-Coupled Receptor Kinase 5 Inhibitor
title_short Identification and Characterization of Amlexanox as a G Protein-Coupled Receptor Kinase 5 Inhibitor
title_sort identification and characterization of amlexanox as a g protein-coupled receptor kinase 5 inhibitor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621012/
https://www.ncbi.nlm.nih.gov/pubmed/25340299
http://dx.doi.org/10.3390/molecules191016937
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