A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion

Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are the two primary intracellular receptors that mediate the effects of the second messenger cAMP. The development of pharmacological tools capable of selectively modulating EPAC activity is a critical unmet need in biological research.

In this study, we describe the identification and characterization of a novel noncyclic nucleotide EPAC antagonist, 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile, termed ESI-09. We demonstrate that ESI-09 specifically blocks intracellular EPAC-mediated activation of Rap1 and phosphorylation of Akt, as well as EPAC-mediated insulin secretion in pancreatic β cells.

Utilizing this novel and specific EPAC inhibitor, we investigated the functional roles of EPAC1 overexpression in pancreatic cancer cells. Our findings reveal that EPAC1 plays a significant role in the migration and invasion of pancreatic cancer cells, suggesting that EPAC1 represents a potential therapeutic target for the development of novel treatment strategies for pancreatic cancer.