Identification of novel, small molecule agonists of cyclic AMP sensor, EPAC1

Interleukin 6 (IL 6) pro-inflammatory trans signalling in vascular endothelial cells (VECs) is associated with the development and progression of atherosclerosis. It was reported that the suppression of IL-6 trans-signalling can be achieved by activation of the exchange protein activated by cyclic AMP 1 (EPAC1), which makes it a very interesting future therapeutic target.
To further investigate the anti-inflammatory effects of EPAC1, new molecular probes are needed, as the only commercially available EPAC1 agonists are cyclic nucleotide analogues. These have many disadvantages, including poor membrane permeability and limited potential for synthetic modifications. In order to address this lack of drug-like, isoform-selective EPAC1 agonists, we screened a library with analogues of I942, a novel, small-molecule non-cyclic AMP EPAC1 agonist first identified by the Yarwood group in 2017. Nine top hits were then tested for agonist activity and three best compounds were selected for the subsequent isoform-selectivity experiments.
Identified analogues show improved binding and agonist activity compared to the parent compound and selectively activate the EPAC1 isoform in cell-based experiments, and are therefore promising leads in the search for new molecular EPAC1 probes.