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  • More and more studies are

    2019-07-11

    More and more studies are focused on the function role of EPAC1 in cancer proliferation, apoptosis and migration. Recently, it was reported that the EPAC-ERK and AKT signaling pathways promote the B cell antigen receptor (BCR) mediated growth arrest and apoptosis in the B lymphoma cell line WEHI-231. In human glioblastoma cell lines A172 and U87MG, EPAC1-Rap1 and PKA pathways mediate cell death and CRT 0066101 what arrest in the process of rolipram regulation of glioblastoma cell density. While in the prostate cancer cells, EPAC1 can increase cell proliferation and survival involved in EPAC/Rap1/B-Raf, Ras/MAPK, and PI3K-mTOR signaling pathways., EPAC is thus crucial in regulating cell migration and proliferation. Numerous papers support that EPAC1 promote various cancer cells (including cervical, fibrosarcoma, melanoma, ovarian, pancreatic and prostate) migration and metastasis. The cAMP-mediated immune functions are well documented, but the breakthrough work on implication of EPAC in anti-cancer immunotherapy has not CRT 0066101 what been reported until recently. EPAC1 was identified to play an essential role in the regulation of T-cell-mediated immunosuppression. Interestingly, results from a recent study suggest that EPAC signaling pathway may up-regulate the aerobic glycolysis, and promote oncogenesis. All these studies demonstrate EPAC1 is an emerging target for cancer therapy. The cAMP signaling controls a wide range of processes in pathogenic bacteria, fungi and protozoa, and cAMP is a critical mediator of microbial pathogens infectious virulence gene expression. It is well known that the functions of cAMP are mainly regulated by EPAC and PKA. Thus, it is not surprising that EPAC has been shown to play a critical role in bacterial infection. For example, according to recent genetic manipulation and pharmacological approaches , knockout EPAC1 gene or inhibition of EPAC1 activity can prevent bacterial adhesion and invasion during fatal rickettsioses. These results offer a new avenue for fighting with bacterial infection and display a novel mode of action for EPAC1 and host-pathogen interactions. Given the essential role of EPAC in various biological functions and human diseases, tremendous efforts have been devoted to discover small molecule EPAC modulators as pharmacological probes and potential drug candidates for the treatment of human diseases. Based on the different chemical structures, currently reported EPAC modulators can be divided into two major categories: cAMP analogues and non-cyclic nucleotide small molecules. Naturally, the cAMP analogues of an EPAC modulator subclass often exhibit EPAC agonist activity, while most of non-cyclic nucleotide ligands tend to act as EPAC antagonists or EPAC inhibitors. Earlier effort on discovery and development of EPAC modulators was mainly focused on design and synthesis of the analogues of compound (cAMP, ), but none of these analogues exhibited selectivity between EPAC and PKA, limiting their usage for further studies. In order to investigate the different biological functions of EPAC and PKA, developing EPAC specific modulators was imperative. A breakthrough on EPAC selective modulators was made by Bos and co-workers, Through the comparison of the binding sites of compound with EPAC and PKA cAMP domains, they found that the 2′-OH group of the compound 1 could form hydrogen bond with highly conserved glutamate residue (Glu238 in human PKA protein) in the PKA cAMP domain, which is absent in the EPAC cAMP binding site (). Interaction between the 2′-OH group and conserved glutamate residue is essential for cAMP binding to the PKA cAMP domain and modification of the 2′-OH group could lead to selective EAPC modulators. Based on these findings, a series of 2′--alkyl-modified analogues of compound , for example, compound 2 (2′--Me-cAMP, ), were designed, and they exhibited about 10- to 100-fold EPAC/PKA selectivity. It is worth to mention that replacing the 2′-OH group by hydrogen led to compound (2′-deoxy-cAMP, ). Compound showed some EPAC/PKA selectivity, but with a dramatic loss of its EPAC activation activity compared to compound .