ArticleBiochemistry2011
A nanomolar-potency small molecule inhibitor of regulator of G-protein signaling proteins.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
46 citing papers in PubMed, 73 citations in OpenAlex.
- 1,2,4-Thiadiazolidin-3,5-Diones as Inhibitors of Cysteine Proteases.Molecules (Basel, Switzerland) · 2025Article
- A multiplex extracellular interactome screening method employing high-avidity nanoparticles.bioRxiv : the preprint server for biology · 2025Article
- Discovery of RGS2-FBXO44 interaction inhibitors using a cell-based NanoBit assay.Molecular pharmacology · 2025Article
- A Phenotypic High-Throughput Screen Identifies Small Molecule Modulators of Endogenous RGS10 in BV-2 Cells.Journal of medicinal chemistry · 2024Article
- A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO.RSC chemical biology · 2024Article
- Exploring Shared Biomarkers of Myocardial Infarction and Alzheimer's Disease via Single-Cell/Nucleus Sequencing and Bioinformatics Analysis.Journal of Alzheimer's disease : JAD · 2023Article
- The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Article
- Fragment-Based Nuclear Magnetic Resonance Screen against a Regulator of G Protein Signaling Identifies a Binding "Hot Spot".Chembiochem : a European journal of chemical biology · 2021Article
- Identification of Small-Molecule Inhibitors of Human Inositol Hexakisphosphate Kinases by High-Throughput Screening.ACS pharmacology & translational science · 2021Article
- Allosteric Pathways Originating at Cysteine Residues in Regulators of G-Protein Signaling Proteins.Biophysical journal · 2021Article
- Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management.Frontiers in molecular neuroscience · 2020Review
- Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials.The Journal of biological chemistry · 2019Review
- An Interhelical Salt Bridge Controls Flexibility and Inhibitor Potency for Regulators of G-protein Signaling Proteins 4, 8, and 19.Molecular pharmacology · 2019Article
- Interplay of cysteine exposure and global protein dynamics in small-molecule recognition by a regulator of G-protein signaling protein.Proteins · 2019Article
- Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures.SLAS discovery : advancing life sciences R & D · 2018Article
- A High-Throughput Time-Resolved Fluorescence Energy Transfer Assay to Screen for Modulators of RGS7/Gβ5/R7BP Complex.Assay and drug development technologies · 2018Article
- Differential Protein Dynamics of Regulators of G-Protein Signaling: Role in Specificity of Small-Molecule Inhibitors.Journal of the American Chemical Society · 2018Article
- Toward Small-Molecule Inhibition of Protein-Protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions.Current topics in medicinal chemistry · 2018Review
- Evaluation of the Selectivity and Cysteine Dependence of Inhibitors across the Regulator of G Protein-Signaling Family.Molecular pharmacology · 2018Article
- The Role of G-proteins and G-protein Regulating Proteins in Depressive Disorders.Frontiers in pharmacology · 2018Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Regulators of G-protein signaling (RGS) proteins are potent negative modulators of signal transduction through G-protein-coupled receptors. They function by binding to activated (GTP-bound) Gα subunits and accelerating the rate of GTP hydrolysis. Modulation of RGS activity by small molecules is an attractive mechanism for fine-tuning GPCR signaling for therapeutic and research purposes. Here we describe the pharmacologic properties and mechanism of action of CCG-50014, the most potent small molecule RGS inhibitor to date. It has an IC(50) for RGS4 of 30 nM and is >20-fold selective for RGS4 over other RGS proteins. CCG-50014 binds covalently to the RGS, forming an adduct on two cysteine residues located in an allosteric regulatory site. It is not a general cysteine alkylator as it does not inhibit activity of the cysteine protease papain at concentrations >3000-fold higher than those required to inhibit RGS4 function. It is also >1000-fold more potent as an RGS4 inhibitor than are the cysteine alkylators N-ethylmaleimide and iodoacetamide. Analysis of the cysteine reactivity of the compound shows that compound binding to Cys(107) in RGS8 inhibits Gα binding in a manner that can be reversed by cleavage of the compound-RGS disulfide bond. If the compound reacts with Cys(160) in RGS8, the adduct induces RGS denaturation, and activity cannot be restored by removal of the compound. The high potency and good selectivity of CCG-50014 make it a useful tool for studying the functional roles of RGS4.
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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.