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  • EPAC activation in VSMCs and ECs reverses several processes


    EPAC activation in VSMCs and ECs reverses several processes involved in the development of in-stent restenosis. Of particular relevance is the ability of EPAC1 to induce SOCS3 gene expression, as SOCS3 exerts multiple protective effects in both cell types, while immunohistochemical studies have shown that neointimal lesions from a pig coronary artery injury model have significantly lower SOCS3 expression levels within proliferating neointimal smooth muscle cells versus those in normal media [81]. Thus, SOCS3 can inhibit VSMC migration, via inhibition of IL-6-mediated induction of matrix metalloproteinase (MMP)-2 and -9 110, 111, and proliferation in vitro, via inhibition of STAT3-mediated induction of cyclin D1 [112] and NH in vivo61, 66. In addition, SOCS3 overexpression can inhibit VSMC inflammation in vitro by inhibiting STAT3 activation [66], while multiple studies have demonstrated that EPAC1-inducible SOCS3 can limit proinflammatory JAK–STAT and ERK1/2 signalling by IL-6 trans-signalling complexes and leptin in VECs 67, 113. Coupled with the well-described ability of EPAC1 to enhance endothelial barrier function [114], localised activation of EPAC1 would be anticipated to suppress NH via inhibition of endothelial inflammation, VSMC proliferation and migration, and remodelling.
    Cyclic adenosine monophosphate (cAMP, ), generated from 2179 by adenylyl cyclase, is a second messenger for intracellular signal transduction in many different organisms. cAMP-mediated signaling events were considered to be transduced largely by protein kinase A (PKA) until the discovery of exchange proteins directly activated by cAMP(EPACs)/cAMP regulated guanine nucleotide exchange factor (cAMP-GEF)., , , These two intracellular receptor families mediated the major physiological effects of cAMP in mammalian cells through the cAMP binding domain (CBD) which acts as a molecular switch for controlling various cellular activities., The identification of EPACs opens new avenues for cAMP signaling research. Unlike PKA, EPAC proteins do not have kinase activity and activate the Ras superfamily small GTPases Rap1 and Rap2 in response to the generation of intracellular cAMP. There are two isoforms of mammalian EPACs, EPAC1 which is more ubiquitously expressed and EPAC2 which is mainly found in CNS, pancreatic islets and adrenal gland. EPAC1 and EPAC2 are structurally homologous but functionally nonredundant. A number of studies have revealed that EPAC proteins are critically involved in a variety of human diseases such as cancer, inflammation, bacterial and viral infections, central nervous system disorders, energy homeostasis and obesity, and cardiac functions., , , , , , Given the physiological and pathophysiological significance of EPAC proteins, the development of pharmacological EPAC modulators is needed. Most EPAC agonists are derivatives of cAMP, while non-cyclic nucleotide ligands usually display EPAC inhibitory activities, except a very recently reported small molecule partial agonist with modest potency. Cheng et al. developed a sensitive and robust fluorescence-based high throughput (HTS) assay, which led to the discovery of a series of non-cyclic nucleotide EPAC inhibitors. After extensive modifications by our team, dihydropyrimidine (HJC0198, ) was obtained with an IC value of 4.0 µM against EPAC2. It selectively blocks cAMP-induced EPAC activation without affecting cAMP-mediated PKA activation at the concentration of 25 µM. Diphenylamine (MAY0132, ), also developed by our team, exhibited potent and selective EPAC2 inhibitory activity with an IC value of 0.4 µM and inhibited cAMP-mediated EPAC2 GEF activity with IC of 1 µM, while displaying no significant inhibition against EPAC1 at 100 µM., Subtype selective compound will not only help understanding diverse functions of EPACs but also may contribute to therapeutic safety in the future, thus further modifications on compound , a good EPAC2 selective inhibitor, are undergoing in our lab. Compound (()-CE3F4, ), identified by Courileau and coworkers via HTS screening, displayed EPAC1 inhibitory activity with an IC value of 4.2 µM with 10-fold selectivity over EPAC2. In our assays, its inhibitory activities against EPAC1 and EPAC2 are 5.5 and 17 µM, respectively. Compound (ESI-09, ) is another promising hit discovered by our team, displaying micromolar inhibitory activities against both EPAC1 and EPAC2., , Herein, we describe the discovery of a series of novel EPAC inhibitors such as compound , which displays enhanced potency against EPAC proteins in comparison with chemical lead .