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  • To develop novel EPAC inhibitors Zhou and co


    To develop novel EPAC inhibitors, Zhou and co-workers optimized the HTS hit as the chemical lead. After modifications of the substituents on the phenyl ring or C6-position of compound , compound () was identified to be the more potent compound in this series with an IC value of 4.0µM (EPAC2). Docking studies revealed that the size and position of substituents played a role in EPAC inhibitory activity. At the concentration of 25µM, compound selectively blocked cAMP-induced EPAC activation and did not inhibit cAMP-mediated PKA activation. In HEK293/EPAC1 and HEK293/EPAC2 cell lines, compound completely blocked EPAC1- and EPAC2-mediated AKT phosphorylation at the concentration of 10µM. Starting from HTS hit , Zhou and co-workers conducted structural modifications to afford compound (), showing an IC of 0.3µM for competitive binding to EPAC2 in the presence of compound . Compound has no inhibitory EPAC1-mediated Rap1-GDP exchange activity or altering cAMP-induced type I and II PKA holoenzymes activation at the concentration of 25µM. This result suggests that compound is an EPAC2-specific inhibitor. Moreover, this conclusion was also confirmed by live cell imaging studies using EPAC1, EPAC2 or PKA FRET sensor. Replacing the -toluenesulfonyl motif in compound with a 4-cholor-3-(trifluoromethyl)aniline group led to compound (). Compound 19 acts as an excellent EPAC2 specific inhibitor with an IC value of 0.4µM (competitively binding to EPAC2 with compound ) and inhibits cAMP-mediated EPAC2 GEF activity with IC of 1µM, showing no significant inhibition of EPAC1 at 100µM. To further identify non-cyclic nucleotide EPAC1 selective inhibitors, the most recent study by this team was focused on compound (). Compound was identified as a non-cyclic nucleotide EPAC1 (IC=3.2µM) and EPAC2 (IC=7.0µM) dual inhibitor. In the meantime, it did not show any effect on PKA even at high concentrations. Furthermore, it is involved in EPAC-mediated Rap1 activation, AKT phosphorylation, pancreatic beta Caspase-2, human recombinant proteinase insulin production and secretion. Although previous work found that the levels of EPAC1 was overexpressed in human pancreatic ductal adenocarcinoma (PDA), the mechanism was unclear. Cheng and co-workers revealed that compound inhibited EPAC1-mediated adhesion of AsPC-1 and PANC-1 cells without affecting cell proliferation and viability. Furthermore, in an orthotopic metastatic mouse model, with an injection dose of 10mg/kg once daily for 3weeks, compound prevented local and distant MIA PaCa-2 cell spread and significantly reduced metastasis to the liver. This result indicates that EPAC1 is a promising target for pancreatic cancer migration and invasion. Cronstein and co-workers revealed that compound completely blocked RANKL-induced osteoclast differentiation at 10µM, and it might diminish bone destruction in inflammatory arthritis. , compound dose-dependently inhibited Freund’s adjuvant (CFA)-induced mechanical hyperalgesia without influencing mechanical sensitivity of control mice, suggesting that compound may be developed as a potential therapy for chronic pain. The essential roles of cAMP-mediated signaling pathways in modulating leptin production/secretin and regulating metabolic homeostasis were previously explored, and the importance of EPAC-cAMP pathway in leptin resistance has been recently discovered. Further studies to investigate EPAC-cAMP pathway in obesity regulation were reported by Cheng and co-workers., Their investigation implies that EPAC inhibitor compound can inhibit leptin production and secretion, and . These findings offer strong evidence that EPAC1 could act as a novel pharmacological target for diabetes and obesity therapies. Recently, Tao et al. found the capacity of compound at a nontoxic concentration (10µM) to protect Calu-3 cells against MERS-CoV and SARS-CoV infection via inhibiting the replication of viral RNA and expression of MERS-CoV and SARS-CoV protein without affecting virus binding to Calu-3 and expression and localization of EPAC protein. Compared wild-type C57BL/6 mice treated with compound (10mg/kg, once daily, i.p. for 12days) group to control group, the survival rate was significantly improved after infection by the mechanism that compound could completely block rickettsial attachment and/or invasion at an early step. Monje and co-workers reported that compound could regulate schwann cell proliferation and differentiation by inhibiting EPAC. In blood stage, compound prevents merozoite invasion of human erythrocytes by inhibiting parasite growth in blood stage. Moreover, Compound can regulate the re-establishment of endothelial and recovery of EC barrier function after thrombin induced hyperpermeability.