Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1

Abstract Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory eff...

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Autores principales:	Euan Parnell, Stuart P. McElroy, Jolanta Wiejak, Gemma L. Baillie, Alison Porter, David R. Adams, Holger Rehmann, Brian O. Smith, Stephen J. Yarwood
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c91ea91952a24175bdc43cc328f5f816
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spelling	oai:doaj.org-article:c91ea91952a24175bdc43cc328f5f8162021-12-02T12:32:53ZIdentification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC110.1038/s41598-017-00455-72045-2322https://doaj.org/article/c91ea91952a24175bdc43cc328f5f8162017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00455-7https://doaj.org/toc/2045-2322Abstract Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory effects within the primary screening assay. Follow-up characterisation by ligand observed nuclear magnetic resonance (NMR) revealed direct interaction of I942 and I178 with EPAC1 and EPAC2-CNBs in vitro. Moreover, in vitro guanine nucleotide exchange factor (GEF) assays revealed that I942 and, to a lesser extent, I178 had partial agonist properties towards EPAC1, leading to activation of EPAC1, in the absence of cAMP, and inhibition of GEF activity in the presence of cAMP. In contrast, there was very little agonist action of I942 towards EPAC2 or protein kinase A (PKA). To our knowledge, this is the first observation of non-cyclic-nucleotide small molecules with agonist properties towards EPAC1. Furthermore, the isoform selective agonist nature of these compounds highlights the potential for the development of small molecule tools that selectively up-regulate EPAC1 activity.Euan ParnellStuart P. McElroyJolanta WiejakGemma L. BaillieAlison PorterDavid R. AdamsHolger RehmannBrian O. SmithStephen J. YarwoodNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Euan Parnell Stuart P. McElroy Jolanta Wiejak Gemma L. Baillie Alison Porter David R. Adams Holger Rehmann Brian O. Smith Stephen J. Yarwood Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1
description	Abstract Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory effects within the primary screening assay. Follow-up characterisation by ligand observed nuclear magnetic resonance (NMR) revealed direct interaction of I942 and I178 with EPAC1 and EPAC2-CNBs in vitro. Moreover, in vitro guanine nucleotide exchange factor (GEF) assays revealed that I942 and, to a lesser extent, I178 had partial agonist properties towards EPAC1, leading to activation of EPAC1, in the absence of cAMP, and inhibition of GEF activity in the presence of cAMP. In contrast, there was very little agonist action of I942 towards EPAC2 or protein kinase A (PKA). To our knowledge, this is the first observation of non-cyclic-nucleotide small molecules with agonist properties towards EPAC1. Furthermore, the isoform selective agonist nature of these compounds highlights the potential for the development of small molecule tools that selectively up-regulate EPAC1 activity.
format	article
author	Euan Parnell Stuart P. McElroy Jolanta Wiejak Gemma L. Baillie Alison Porter David R. Adams Holger Rehmann Brian O. Smith Stephen J. Yarwood
author_facet	Euan Parnell Stuart P. McElroy Jolanta Wiejak Gemma L. Baillie Alison Porter David R. Adams Holger Rehmann Brian O. Smith Stephen J. Yarwood
author_sort	Euan Parnell
title	Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1
title_short	Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1
title_full	Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1
title_fullStr	Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1
title_full_unstemmed	Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1
title_sort	identification of a novel, small molecule partial agonist for the cyclic amp sensor, epac1
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c91ea91952a24175bdc43cc328f5f816
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Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1

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