ArticleACS chemical biology2015
Identification and structure-function analysis of subfamily selective G protein-coupled receptor kinase inhibitors.
Article in ACS chemical biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 65 citations in OpenAlex.
- An Experimentally Validated Structure-Based Virtual Screening Approach to Identify Nucleotide-Binding Protein Inhibitors as a New Source of Kinase Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Comparative Phosphoproteomic Profiling and Network-based Interactome Analysis of GRK5 and GRK6.Cell biochemistry and biophysics · 2026Article
- Cell-based and isoform-selective G protein-coupled receptor kinase assays for comprehensive inhibitor evaluation.Communications biology · 2026Article
- High-Throughput Cardiac Hypertrophy Phenotyping Supports Lead Optimization of GRK5 Inhibitors.ACS medicinal chemistry letters · 2026Article
- Potent, Selective, and Drug-Like G Protein-Coupled Receptor Kinase 5 and 6 Inhibitors: Design, Synthesis, and X-Ray Structural Studies.ChemMedChem · 2025Article
- Nuclear-Localized BCKDK Facilitates Homologous Recombination Repair to Support Breast Cancer Progression and Therapy Resistance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure.Acta physiologica (Oxford, England) · 2025Review
- Astragaloside IV protects brain cells from ischemia-reperfusion injury by inhibiting ryanodine receptor expression and reducing the expression of P-Src and P-GRK2.Scientific reports · 2024Article
- QSAR via multisite λ-dynamics in the orphaned TSSK1B kinase.Protein science : a publication of the Protein Society · 2023Article
- Application of Biobased Solvents in Asymmetric Catalysis.Molecules (Basel, Switzerland) · 2022Review
- Targeted inhibition of GRK2 kinase domain by CP-25 to reverse fibroblast-like synoviocytes dysfunction and improve collagen-induced arthritis in rats.Acta pharmaceutica Sinica. B · 2021Article
- The Open Question of How GPCRs Interact with GPCR Kinases (GRKs).Biomolecules · 2021Article
- Synthesis, crystal structure and antibacterial studies of dihydropyrimidines and their regioselectively oxidized products.RSC advances · 2021Article
- Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure.ESC heart failure · 2020Article
- A New Paroxetine-Based GRK2 Inhibitor Reduces Internalization of theMolecular pharmacology · 2020Article
- Pleiotropic Properties of Amphiphilic Dihydropyridines, Dihydropyridones, and Aminovinylcarbonyl Compounds.Oxidative medicine and cellular longevity · 2020Article
- Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors.ACS medicinal chemistry letters · 2019Article
- G protein-coupled receptor kinases as therapeutic targets in the heart.Nature reviews. Cardiology · 2019Review
- Computational study of paroxetine-like inhibitors reveals new molecular insight to inhibit GRK2 with selectivity over ROCK1.Scientific reports · 2019Article
- Fluorescence-based investigations of RNA-small molecule interactions.Methods (San Diego, Calif.) · 2019Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Selective inhibitors of individual subfamilies of G protein-coupled receptor kinases (GRKs) would serve as useful chemical probes as well as leads for therapeutic applications ranging from heart failure to Parkinson's disease. To identify such inhibitors, differential scanning fluorimetry was used to screen a collection of known protein kinase inhibitors that could increase the melting points of the two most ubiquitously expressed GRKs: GRK2 and GRK5. Enzymatic assays on 14 of the most stabilizing hits revealed that three exhibit nanomolar potency of inhibition for individual GRKs, some of which exhibiting orders of magnitude selectivity. Most of the identified compounds can be clustered into two chemical classes: indazole/dihydropyrimidine-containing compounds that are selective for GRK2 and pyrrolopyrimidine-containing compounds that potently inhibit GRK1 and GRK5 but with more modest selectivity. The two most potent inhibitors representing each class, GSK180736A and GSK2163632A, were cocrystallized with GRK2 and GRK1, and their atomic structures were determined to 2.6 and 1.85 Å spacings, respectively. GSK180736A, developed as a Rho-associated, coiled-coil-containing protein kinase inhibitor, binds to GRK2 in a manner analogous to that of paroxetine, whereas GSK2163632A, developed as an insulin-like growth factor 1 receptor inhibitor, occupies a novel region of the GRK active site cleft that could likely be exploited to achieve more selectivity. However, neither compound inhibits GRKs more potently than their initial targets. This data provides the foundation for future efforts to rationally design even more potent and selective GRK inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.