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  • In addition PK studies on indicate that it

    2019-11-07

    In addition, PK studies on indicate that it displays excellent bioavailability, pharmacological and toxicological parameters., A concern was initially raised about compound that it may cause EPAC denaturing properties and false positives. To address this issue, Cheng and co-workers have conducted a battery of biochemical and pharmacological characterizations of compound , and further validated this compound as an EPAC specific inhibitor. Compound has been widely used as a useful chemical probe to elucidate the role of EPAC in anti-cancer migration, anti-inflammation, anti-obesity, antivirus, anti-bacteria and other diseases. A preliminary structure-activity relationship (SAR) of compound revealed that choro Fisetin at C3-position of phenyl ring was essential for the EPAC inhibitory activities. Replacing the choro atom at C3-position of phenyl ring with hydrogen atom led to compound (IC=59.8µM) (), with about 6-fold activity loss of EPAC2 inhibition. Adding another Cl atom at 5-position of compound led to compound (). The IC value of compound (IC=1.9µM for EPAC2) was about 5-fold improvement compared to compound . Further, Zhou and co-workers. systematically investigated SAR of compound . Alteration of the linker and modification of the substitutes on isoxazole ring resulted in a dramatic activity loss. However, a slightly modification on the phenyl ring by addition of a third choro atom on compound afforded compound (). Compound was proved to be a potent compound with an IC value of 0.9µM for EPAC2 inhibition. In addition, it also showed a high EPAC1 inhibitory effect with an IC value of 2.4µM. Molecular docking studies show that compound could form hydrophobic and hydrogen bond interactions with EPAC2 CBD., The motif on the isoxazole ring can stretch into the hydrophobic pocket and form hydrophobic interactions with residues of Phe367, Leu406, Ala407 and Ala415, while the phenyl moiety occupies and interacts with the hydrophobic pocket consisting of Val386 and Leu397. Moreover, there is a crucial hydrogen bond between NH of the linker and the side oxygen atom of residue Asp402. Meanwhile, Courilleau et al. identified a tetrahydroquinoline derivative, named as CE3F4 (), from the chimiothèque essentielle compound library () as an EPAC inhibitor. In intact cells, it showed certain inhibitory activity in EPAC1 GEF without affecting the PKA activity. Further, compound was reported to exhibit modest selectivity on EPAC1 versus EPAC2, providing an EPAC1 selective inhibitor. An early SAR study indicated that the substituents on the tetrahydroquinoline pharmacophore was requisite for the EPAC1 inhibitory activity. The stereochemistry also plays an important role in EPAC1 inhibitory activity, and its ()-enantiomer () was found to be 10-fold more potent than its ()-enantiomer () in EPAC1 GEF inhibition . In addition, compound exhibits 10-fold selectivity for EPAC1 versus EPAC2. Compound may serve as a useful chemical probe for elucidating biological functions of EPAC1, while more relevant studies are needed to further validate its target-specificity and therapeutic potential. It is almost two decades since the discovery of EPAC as an important regulator of the cAMP-mediated biological function processes. Major advances have been made in understanding the function roles of EPACs with the aid of genetic knockout and pharmacological manipulations in various pathogenic models. Moreover, recent findings reveal the critical roles of EPACs in the manifestation of diverse maladies including cancer, diabetes and obesity, heart failure, inflammation, pain, infections, and CNS disorders, suggesting that EPAC presents a promising target for the treatment of various diseases. X-ray co-crystal analysis and NMR spectroscopy not only provide the molecular clues of EPAC activation, but also give researcher a clear vision of the binding modes of EPAC proteins with their modulators. For example, the first breakthrough work on development of EPAC activator compound through rational design facilitated by the co-crystal structural analysis of compound and EPAC2. Although compound and its prodrug have been useful as pharmacological tools for probing cAMP-mediated signaling, the big challenge is that it exhibits cross-target activities and off-target effects. Thus, the therapeutic applications of such cAMP analogues as EPAC agonists are potentially limited.