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J. Cardiovasc. Dev. Dis. 2017, 4(4), 22; doi:10.3390/jcdd4040022

The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation

1
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK
2
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
3
Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh EH14 4AS, UK
*
Author to whom correspondence should be addressed.
Received: 7 November 2017 / Revised: 23 November 2017 / Accepted: 30 November 2017 / Published: 5 December 2017
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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Abstract

The cyclic 3′,5′-adenosine monophosphate (cAMP) sensor enzyme, EPAC1, is a candidate drug target in vascular endothelial cells (VECs) due to its ability to attenuate proinflammatory cytokine signalling normally associated with cardiovascular diseases (CVDs), including atherosclerosis. This is through the EPAC1-dependent induction of the suppressor of cytokine signalling gene, SOCS3, which targets inflammatory signalling proteins for ubiquitinylation and destruction by the proteosome. Given this important role for the EPAC1/SOCS3 signalling axis, we have used high throughput screening (HTS) to identify small molecule EPAC1 regulators and have recently isolated the first known non-cyclic nucleotide (NCN) EPAC1 agonist, I942. I942 therefore represents the first in class, isoform selective EPAC1 activator, with the potential to suppress pro-inflammatory cytokine signalling with a reduced risk of side effects associated with general cAMP-elevating agents that activate multiple response pathways. The development of augmented I942 analogues may therefore provide improved research tools to validate EPAC1 as a potential therapeutic target for the treatment of chronic inflammation associated with deadly CVDs. View Full-Text
Keywords: EPAC1; cyclic AMP; cyclic nucleotide binding domain; inflammation; endothelial cells; high-throughput screening EPAC1; cyclic AMP; cyclic nucleotide binding domain; inflammation; endothelial cells; high-throughput screening
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MDPI and ACS Style

Barker, G.; Parnell, E.; van Basten, B.; Buist, H.; Adams, D.R.; Yarwood, S.J. The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation. J. Cardiovasc. Dev. Dis. 2017, 4, 22.

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