title: Identification and characterization of amlexanox as a G protein-coupled receptor kinase 5 inhibitor.
abstract: 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.
authors.affiliation: Life Sciences Institute and the Departments of Pharmacology and Biological Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kristoff T
authors.initials: KT
authors.lastname: Homan
authors.affiliation: Life Sciences Institute and the Departments of Pharmacology and Biological Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Wu
authors.affiliation: Center for Translation Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cannavo
authors.affiliation: Center for Translation Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Life Sciences Institute and the Departments of Pharmacology and Biological Sciences, University of Michigan, Ann Arbor, MI 48109, USA. tesmerjj@umich.edu.
authors.forename: John J G
authors.initials: JJ
authors.lastname: Tesmer
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D018926:Anti-Allergic Agents / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000737:chemistry / Q000378:metabolism; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D018926:Anti-Allergic Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C045742:amlexanox; D051606:G-Protein-Coupled Receptor Kinase 1; D054774:G-Protein-Coupled Receptor Kinase 5