ArticleThe Journal of biological chemistry2014
Allosteric inhibition of Epac: computational modeling and experimental validation to identify allosteric sites and inhibitors.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- Review
- Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.Pharmacological reviews · 2025Review
- Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis.The EMBO journal · 2020Article
- Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics.Journal of computer-aided molecular design · 2020Article
- Review
- Targeting the Small GTPase Superfamily through Their Regulatory Proteins.Angewandte Chemie (International ed. in English) · 2020Review
- Review
- Review
- Article
- Selective small-molecule EPAC activators.Biochemical Society transactions · 2019Review
- The novel exchange protein activated by cyclic AMP 1 (EPAC1) agonist, I942, regulates inflammatory gene expression in human umbilical vascular endothelial cells (HUVECs).Biochimica et biophysica acta. Molecular cell research · 2019Article
- Druggable targets in the Rho pathway and their promise for therapeutic control of blood pressure.Pharmacology & therapeutics · 2019Review
- Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment.Molecular and cellular biochemistry · 2018Review
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation.Journal of cardiovascular development and disease · 2017Review
- Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1.Scientific reports · 2017Article
- The role of Epac in the heart.Cellular and molecular life sciences : CMLS · 2017Review
- Functionalized N,N-Diphenylamines as Potent and Selective EPAC2 Inhibitors.ACS medicinal chemistry letters · 2016Article
- The future of EPAC-targeted therapies: agonism versus antagonism.Trends in pharmacological sciences · 2015Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is an effector of cAMP signaling and has been implicated to have roles in numerous diseases, including diabetes mellitus, heart failure, and cancer. We used a computational molecular modeling approach to predict potential binding sites for allosteric modulators of Epac and to identify molecules that might bind to these regions. This approach revealed that the conserved hinge region of the cyclic nucleotide-binding domain of Epac1 is a potentially druggable region of the protein. Using a bioluminescence resonance energy transfer-based assay (CAMYEL, cAMP sensor using YFP-Epac-Rluc), we assessed the predicted compounds for their ability to bind Epac and modulate its activity. We identified a thiobarbituric acid derivative, 5376753, that allosterically inhibits Epac activity and used Swiss 3T3 and HEK293 cells to test the ability of this compound to modulate the activity of Epac and PKA, as determined by Rap1 activity and vasodilator-stimulated phosphoprotein phosphorylation, respectively. Compound 5376753 selectively inhibited Epac in biochemical and cell migration studies. These results document the utility of a computational approach to identify a domain for allosteric regulation of Epac and a novel compound that prevents the activation of Epac1 by cAMP.
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What OpenQuestion holds
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.