Identification of A Novel Class of Benzofuran Oxoacetic Acid-Derived Ligands that Selectively Activate Cellular EPAC1

Elizabeth M Beck1, Euan Parnell2, Angela Cowley1

  • 1European Screening Centre Newhouse, University of Dundee, Biocity Scotland, Bo'Ness Road, Newhouse, Lanarkshire ML1 5UH, UK.

Cells
|November 16, 2019
PubMed

Insights

Researchers identified SY009, a novel non-cyclic nucleotide activator, that selectively targets EPAC1 (Exchange protein directly activated by cAMP 1). This discovery offers potential therapeutic strategies for diabetes and cardiovascular diseases by modulating Rap GTPase signaling.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclic AMP (cAMP) activates EPAC1 and EPAC2, which regulate Rap GTPases controlling crucial cellular functions.
  • EPAC1 and EPAC2 activation holds therapeutic potential for diabetes and cardiovascular diseases.
  • Developing synthetic agonists for EPAC1 and EPAC2 is a key research objective.

Purpose of the Study:

  • To identify novel EPAC agonists using a high-throughput screening assay.
  • To characterize the potency and selectivity of identified EPAC1 binders.
  • To validate novel compounds as EPAC1 activators in cellular assays.

Main Methods:

  • Ultra-high-throughput screening (uHTS) assay utilizing a fluorescent cAMP analogue (8-NBD-cAMP) to detect EPAC1 CNBD binding.
  • Synthesis and testing of a library of SY000 analogues, including SY009.
  • Orthogonal assays such as competition binding, microscale thermophoresis, in vitro activity assays, and Rap1 GTPase activation assays.

Main Results:

  • A benzofuran oxaloacetic acid derivative, SY000, was identified as a moderate EPAC1 binder.
  • SY009, an analogue of SY000, demonstrated a 10-fold increase in EPAC1 binding potency.
  • SY009 confirmed as an EPAC1 agonist in vitro and selectively activated EPAC1 over EPAC2 in cellular assays.

Conclusions:

  • SY009 represents a new class of non-cyclic nucleotide (NCN) EPAC1 activators.
  • The selective activation of EPAC1 by SY009 provides a promising avenue for therapeutic development.
  • Further research into NCN EPAC1 activators could lead to novel treatments for cAMP-mediated diseases.

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