ESI-09

ESI-09 is a specific exchange protein directly activated by cAMP (EPAC) inhibitor with IC50 of 3.2 μM and 1.4 μM for EPAC1 and EPAC2, respectively, >100-fold selectivity over PKA.ESI-09 is a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer.

Epac-inhibitors: facts and artefacts.
Rehmann H1. Sci Rep. 2013 Oct 23;3:3032. doi: 10.1038/srep03032.
cAMP is a universal second messenger. Its signalling is mediated by protein kinase A, Epac and certain types of ion channels in mammalians. cAMP signalling is involved in many physiological processes ranging from vision to the control of insulin secretion, pacemaker activity and gene transcription and therefore selective pharmacological interference is of medical interest. Whereas selective inhibitors of PKA and selective activators of Epac are well established, no inhibitors of Epac were available until recently. Here the action of four of the novel Epac inhibitors was analysed by biophysical means. ESI-05 is confirmed as a selective inhibitor of Epac2. No direct action of Brefeldin A on Epac could be demonstrated. ESI-09 and HJC0197 were found to act as chemicals with general protein denaturing properties and do not act on Epac selectively.