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Sci Rep. 2015 Mar 20;5:9344. doi: 10.1038/srep09344.

Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window".

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Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030.
Chemical Biology Program, Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas 77555-0615.
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8S 4M1, Canada.
1] Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8S 4M1, Canada [2] Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, L8S 4M1, Canada.


The cAMP signaling cascade is one of the most frequently targeted pathways for the development of pharmaceutics. A plethora of recent genetic and pharmacological studies suggest that exchange proteins directly activated by cAMP (EPACs) are implicated in multiple pathologies. Selective EPAC inhibitors have been recently developed. One specific inhibitor, ESI-09, has been shown to block EPAC activity and functions, as well as to recapitulate genetic phenotypes of EPAC knockout mice when applied in vivo. However, a recent study raised concern that ESI-09 might act as a non-specific protein denaturant. Herein, we present a detailed biochemical and pharmacological characterization, as well as a structure-activity relationship (SAR) analysis of ESI-09. Our studies show that ESI-09 dose-dependently inhibits activity of both EPAC1 and EPAC2 with apparent IC50 values well below the concentrations shown to induce "protein denaturation". Moreover, the ESI-09's action towards EPAC proteins is highly sensitive to minor modifications of the 3-chlorophenyl moiety. Taken together, these results demonstrate that ESI-09 indeed acts as an EPAC specific antagonist and does not significantly destabilize/denature proteins at pharmacological effective concentrations. This conclusion is further supported by NMR data showing that ESI-09 induces residue-dependent chemical shift changes at low concentrations, while preserving well dispersed peaks.

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