Development of small-molecule regulators of inflammatory signalling

Interleukin-6 (IL-6) pro-inflammatory trans-signalling in vascular endothelial cells (VECs) is associated with the development and progression of atherosclerosis. The pro-inflammatory actions of IL-6 can be inhibited by induction of the suppressor of cytokine signalling 3 (SOCS-3) gene. SOCS3 gene is induced by the second messenger, cyclic AMP, which acts through the enzyme, exchange protein activated by cyclic AMP 1 (EPAC1). When activated by cyclic AMP, EPAC1 serves as a guanine nucleotide exchange factor for the small GTPases Rap1 and Rap2. Active Rap proteins then promote the production of the SOCS3 protein. The ability of EPAC1 to induce SOCS3 and reduce inflammation in VECs by suppressing IL-6 trans-signalling makes them very interesting future therapeutic targets
To further investigate this signalling pathway new molecular probes are needed. The only available EPAC1 agonists are cyclic AMP analogues, which have many disadvantages, including poor membrane permeability and metabolic stability. In 2017, the Yarwood group identified a novel, small-molecule non-cyclic AMP EPAC1 agonist, I942. We now want to address the lack of drug-like, isoform-selective EPAC1 agonists by synthesizing a range of I942 derivatives to obtain molecules with improved characteristics. My research is currently focused on developing methods for screening and characterizing I942 analogues.