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

• Published in: Journal of cardiovascular development and disease Vol. 4; no. 4; p. 22
• Main Authors: Barker, Graeme, Parnell, Euan, van Basten, Boy, Buist, Hanna, Adams, David R, Yarwood, Stephen J
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 05.12.2017; MDPI AG
• Subjects: cyclic AMP; cyclic nucleotide binding domain; endothelial cells; EPAC1; high-throughput screening; inflammation; Review; cyclic nucleotide binding domain; cyclic AMP; endothelial cells; EPAC1; inflammation; high-throughput screening
• ISSN: 2308-3425; 2308-3425
• DOI: 10.3390/jcdd4040022

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.