Abstract
Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), 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. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that 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.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medicine [Grant R01GM066170], a training fellowship from the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia funded by the National Institutes of Health National Institute of General Medicine [Grant T32GM089657] and, in part, by the John S. Dunn Foundation through the Gulf Coast Consortium for Chemical Genomics.
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This article has supplemental material available at molpharm.aspetjournals.org.
- Received June 17, 2012.
- Accepted October 11, 2012.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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