Identification of a novel class of benzofuran oxoacetic acid-derived ligands that selectively activate cellular EPAC1

Elizabeth M. Beck, Euan Parnell, Angela Cowley, Alison Porter, Jonathan Gillespie, John Robinson, Lindsay Robinson, Andrew D. Pannifer, Veronique Hamon, Philip Jones, Angus Morrison, Stuart McElroy, Martin Timmerman, Helma Rutjes, Pravin Mahajan, Jolanta Wiejak, Urszula Luchowska-Stańska, David Morgan, Graeme Barker, Holger RehmannStephen J. Yarwood*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Cyclic AMP promotes EPAC1 and EPAC2 activation through direct binding to a specific cyclic nucleotide-binding domain (CNBD) within each protein, leading to activation of Rap GTPases, which control multiple cell responses, including cell proliferation, adhesion, morphology, exocytosis, and gene expression. As a result, it has become apparent that directed activation of EPAC1 and EPAC2 with synthetic agonists may also be useful for the future treatment of diabetes and cardiovascular diseases. To identify new EPAC agonists we have developed a fluorescent-based, ultra-high-throughput screening (uHTS) assay that measures the displacement of binding of the fluorescent cAMP analogue, 8-NBD-cAMP to the EPAC1 CNBD. Triage of the output of an approximately 350,000 compound screens using this assay identified a benzofuran oxaloacetic acid EPAC1 binder (SY000) that displayed moderate potency using orthogonal assays (competition binding and microscale thermophoresis). We next generated a limited library of 91 analogues of SY000 and identified SY009, with modifications to the benzofuran ring associated with a 10-fold increase in potency towards EPAC1 over SY000 in binding assays. In vitro EPAC1 activity assays confirmed the agonist potential of these molecules in comparison with the known EPAC1 non-cyclic nucleotide (NCN) partial agonist, I942. Rap1 GTPase activation assays further demonstrated that SY009 selectively activates EPAC1 over EPAC2 in cells. SY009 therefore represents a novel class of NCN EPAC1 activators that selectively activate EPAC1 in cellulae.

Original languageEnglish (US)
Article number1425
Issue number11
StatePublished - Nov 2019


  • Agonists
  • Cyclic AMP
  • EPAC
  • Guanine nucleotide exchange factor (GEF) activity
  • Rap1
  • UHTS

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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