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Research ArticleArticle

A Novel EPAC-Specific Inhibitor Suppresses Pancreatic Cancer Cell Migration and Invasion

Muayad Almahariq, Tamara Tsalkova, Fang C. Mei, Haijun Chen, Jia Zhou, Sarita K. Sastry, Frank Schwede and Xiaodong Cheng
Molecular Pharmacology January 2013, 83 (1) 122-128; DOI: https://doi.org/10.1124/mol.112.080689
Muayad Almahariq
Department of Pharmacology and Toxicology (M.A., T.T., F.C.M., H.C., J.Z., X.C.) and Sealy Center for Structural Biology and Molecular Biophysics (X.C.), Department of Biochemistry and Molecular Biology (S.K.S.), The University of Texas Medical Branch, Galveston, Texas; and BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Bremen, Germany (F.S.)
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Tamara Tsalkova
Department of Pharmacology and Toxicology (M.A., T.T., F.C.M., H.C., J.Z., X.C.) and Sealy Center for Structural Biology and Molecular Biophysics (X.C.), Department of Biochemistry and Molecular Biology (S.K.S.), The University of Texas Medical Branch, Galveston, Texas; and BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Bremen, Germany (F.S.)
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Fang C. Mei
Department of Pharmacology and Toxicology (M.A., T.T., F.C.M., H.C., J.Z., X.C.) and Sealy Center for Structural Biology and Molecular Biophysics (X.C.), Department of Biochemistry and Molecular Biology (S.K.S.), The University of Texas Medical Branch, Galveston, Texas; and BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Bremen, Germany (F.S.)
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Haijun Chen
Department of Pharmacology and Toxicology (M.A., T.T., F.C.M., H.C., J.Z., X.C.) and Sealy Center for Structural Biology and Molecular Biophysics (X.C.), Department of Biochemistry and Molecular Biology (S.K.S.), The University of Texas Medical Branch, Galveston, Texas; and BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Bremen, Germany (F.S.)
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Jia Zhou
Department of Pharmacology and Toxicology (M.A., T.T., F.C.M., H.C., J.Z., X.C.) and Sealy Center for Structural Biology and Molecular Biophysics (X.C.), Department of Biochemistry and Molecular Biology (S.K.S.), The University of Texas Medical Branch, Galveston, Texas; and BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Bremen, Germany (F.S.)
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Sarita K. Sastry
Department of Pharmacology and Toxicology (M.A., T.T., F.C.M., H.C., J.Z., X.C.) and Sealy Center for Structural Biology and Molecular Biophysics (X.C.), Department of Biochemistry and Molecular Biology (S.K.S.), The University of Texas Medical Branch, Galveston, Texas; and BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Bremen, Germany (F.S.)
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Frank Schwede
Department of Pharmacology and Toxicology (M.A., T.T., F.C.M., H.C., J.Z., X.C.) and Sealy Center for Structural Biology and Molecular Biophysics (X.C.), Department of Biochemistry and Molecular Biology (S.K.S.), The University of Texas Medical Branch, Galveston, Texas; and BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Bremen, Germany (F.S.)
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Xiaodong Cheng
Department of Pharmacology and Toxicology (M.A., T.T., F.C.M., H.C., J.Z., X.C.) and Sealy Center for Structural Biology and Molecular Biophysics (X.C.), Department of Biochemistry and Molecular Biology (S.K.S.), The University of Texas Medical Branch, Galveston, Texas; and BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Bremen, Germany (F.S.)
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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.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • dx.doi.org/10.1124/mol.112.080689.

  • Received June 17, 2012.
  • Accepted October 11, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (1)
Molecular Pharmacology
Vol. 83, Issue 1
1 Jan 2013
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Research ArticleArticle

Characterization of an EPAC-Specific Inhibitor

Muayad Almahariq, Tamara Tsalkova, Fang C. Mei, Haijun Chen, Jia Zhou, Sarita K. Sastry, Frank Schwede and Xiaodong Cheng
Molecular Pharmacology January 1, 2013, 83 (1) 122-128; DOI: https://doi.org/10.1124/mol.112.080689

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Research ArticleArticle

Characterization of an EPAC-Specific Inhibitor

Muayad Almahariq, Tamara Tsalkova, Fang C. Mei, Haijun Chen, Jia Zhou, Sarita K. Sastry, Frank Schwede and Xiaodong Cheng
Molecular Pharmacology January 1, 2013, 83 (1) 122-128; DOI: https://doi.org/10.1124/mol.112.080689
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