Identification of a novel, small molecule partial agonist for the cyclic AMP sensor, EPAC1

Parnell, E., McElroy, S. P., Wiejak, J., Baillie, G. L., Porter, A., Adams, D. R., Rehmann, H., Smith, B. O. and Yarwood, S. J. (2017) Identification of a novel, small molecule partial agonist for the cyclic AMP sensor, EPAC1. Scientific Reports, 7, 294. (doi:10.1038/s41598-017-00455-7) (PMID:28331191) (PMCID:PMC5428521)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Yarwood, Dr Stephen and Parnell, Mr Euan and Smith, Dr Brian and Wiejak, Dr Jolanta
Authors: Parnell, E., McElroy, S. P., Wiejak, J., Baillie, G. L., Porter, A., Adams, D. R., Rehmann, H., Smith, B. O., and Yarwood, S. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Scientific Reports 7:294
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
500151Doctoral Training Grant 2009-15Timothy PalmerBiotechnology and Biological Sciences Research Council (BBSRC)BB/F016735/1RI CARDIOVASCULAR & MEDICAL SCIENCES
683671Regulation of Anti-inflammatory Gene Expression in Vascular Endothelial Cells by EPAC1Stephen YarwoodBritish Heart Foundation (BHF)PG/15/15/31316RI MOLECULAR CELL & SYSTEMS BIOLOGY