Recent Advances in the Discovery of Small Molecules Targeting Exchange Proteins Directly Activated by cAMP (EPAC)

Abstract

cAMP is a pivotal second messenger that regulates numerous biological processes under physiological and pathological conditions, including cancer, diabetes, heart failure, inflammation and neurological disorders. In the past, all effects of cAMP were initially believed to be mediated by PKA and cyclic nucleotide-regulated ion channels. Since the discovery of EPAC proteins in 1998, accumulating evidence has demonstrated that the net cellular effects of cAMP are also regulated by EPAC. The pursuit of the biological functions of EPAC has benefited from the development and applications of a growing number of pharmacological probes targeting EPAC proteins. In this Perspective, we seek to provide a concise update on recent advances in the development of chemical entities including various membrane-permeable analogues of cAMP and newly discovered EPAC-specific ligands from high throughput assays and hit-to-lead optimizations.

Identification of novel 2-(benzo[ d ]isoxazol-3-yl)-2-oxo- N -phenylacetohydrazonoyl cyanide analoguesas potent EPAC antagonists

“…Given the only available X-ray crystal structures of inactive and active EPAC2 proteins [27, 28], molecular docking studies of compounds 1 , 10 and 33 at CBD-B of active EPAC2 protein (PDB Code 3CF6) were performed to investigate the predicted binding modes using the Schrödinger Small-Molecule Drug Discovery Suite [23]. Although this algorithm slightly differs from our previously employed AutoDock Vina [7, 24], the docking results are generally consistent with the previous studies. The current docking results also reveal that these new compounds fit well into the functional CBD-B binding pocket of active EPAC2 (Fig.…”

“…EPAC1 is more ubiquitously expressed, whereas the expression of EPAC2 is relatively restricted, mainly found in brain, pancreatic islets and adrenal gland [2]. From nearly two decades of research on EPAC, accumulating studies, including those with the aid of small-molecule EPAC modulators [7, 8] such as various cAMP analogues (e.g. 007-AM [9]) and newly discovered EPAC-specific antagonists (e.g.…”

“…1) has been shown to selectively inhibit EPAC functions in vitro [12] and in vivo [13, 14]. With the aid of molecular docking studies of 1 into the cAMP binding domain B of active EPAC2 proteins, we hypothesized that binding interactions of inhibitors to EPAC2 proteins may primarily occur through two terminal hydrophobic pockets (P1 and P2) and the unique linker [7]. Later, systematic structure-activity–relationships (SARs) studies were performed, leading to the discovery of several more active EPAC antagonists (e.g., 2 (NY0123)) with low micromolar inhibitory activity and improved solubility [24].…”

Structure-activity relationships of 2-substituted phenyl- N -phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs)

“…15 Most EPAC agonists are derivatives of cAMP, 16 while non-cyclic nucleotide ligands usually display EPAC inhibitory activities, except a very recently reported small molecule partial agonist with modest potency. 17 Cheng, et al developed a sensitive and robust fluorescence-based high throughput (HTS) assay, 18 which led to the discovery of a series of non-cyclic nucleotide EPAC inhibitors.…”

“…29 Docking studies of compound 5 into the cAMP binding domain of active EPAC2 suggested that 3-chloro phenyl ring A and tert -butylisoxazole occupy two hydrophobic pockets and play important roles for their interaction. 15 Compound 6 was synthesized and gave an IC 50 value of 13.3 μM, showing the phenyl bioisosteric replacement was a viable route forward.…”