title: Epac-inhibitors: facts and artefacts.
abstract: cAMP is a universal second messenger. Its signalling is mediated by protein kinase A, Epac and certain types of ion channels in mammalians. cAMP signalling is involved in many physiological processes ranging from vision to the control of insulin secretion, pacemaker activity and gene transcription and therefore selective pharmacological interference is of medical interest. Whereas selective inhibitors of PKA and selective activators of Epac are well established, no inhibitors of Epac were available until recently. Here the action of four of the novel Epac inhibitors was analysed by biophysical means. ESI-05 is confirmed as a selective inhibitor of Epac2. No direct action of Brefeldin A on Epac could be demonstrated. ESI-09 and HJC0197 were found to act as chemicals with general protein denaturing properties and do not act on Epac selectively.
authors.affiliation: Molecular Cancer Research, Centre of Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Holger
authors.initials: H
authors.lastname: Rehmann
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology*; D020126:Brefeldin A / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D011489:Protein Denaturation; D013450:Sulfones / Q000494:pharmacology*; D013816:Thermodynamics; D044366:Transition Temperature
chemical_list: C579558:3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile; D001555:Benzene Derivatives; C000589230:ESI-05; D020662:Guanine Nucleotide Exchange Factors; D006835:Hydrazones; D007555:Isoxazoles; C116122:RAPGEF3 protein, human; C485746:RAPGEF6 protein, human; C486707:Rapgef4 protein, mouse; D013450:Sulfones; D020126:Brefeldin A; D000242:Cyclic AMP