2. Academic Validation
  3. The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation

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

  • J Cardiovasc Dev Dis. 2017 Dec 5;4(4):22. doi: 10.3390/jcdd4040022.
Graeme Barker 1,  Euan Parnell 2,  Boy van Basten 3,  Hanna Buist 4,  David R Adams 5,  Stephen J Yarwood 6
Affiliations

Affiliations

  • 1 Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK. [email protected].
  • 2 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. [email protected].
  • 3 Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh EH14 4AS, UK. [email protected].
  • 4 Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh EH14 4AS, UK. [email protected].
  • 5 Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK. [email protected].
  • 6 Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh EH14 4AS, UK. [email protected].
PMID: 29367551 DOI: 10.3390/jcdd4040022
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.

Keywords

EPAC1; cyclic AMP; cyclic nucleotide binding domain; endothelial cells; high-throughput screening; inflammation.

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