The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh EH14 4AS, UK
Author to whom correspondence should be addressed.
J. Cardiovasc. Dev. Dis. 2017, 4(4), 22; https://doi.org/10.3390/jcdd4040022
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)
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.