Synthesis and Biochemical Evaluation of Noncyclic Nucleotide Exchange Proteins Directly Activated by cAMP 1 (EPAC1) Regulators

Pingyuan Wang, Urszula Luchowska-Stańska, Boy Van Basten, Haiying Chen, Zhiqing Liu, Jolanta Wiejak, Padraic Whelan, David Morgan, Emma Lochhead, Graeme Barker, Holger Rehmann, Stephen J. Yarwood, Jia Zhou

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Exchange proteins directly activated by cAMP (EPAC) play a central role in various biological functions, and activation of the EPAC1 protein has shown potential benefits for the treatment of various human diseases. Herein, we report the synthesis and biochemical evaluation of a series of noncyclic nucleotide EPAC1 activators. Several potent EPAC1 binders were identified including 25g, 25q, 25n, 25u, 25e, and 25f, which promote EPAC1 guanine nucleotide exchange factor activity in vitro. These agonists can also activate EPAC1 protein in cells, where they exhibit excellent selectivity toward EPAC over protein kinase A and G protein-coupled receptors. Moreover, 25e, 25f, 25n, and 25u exhibited improved selectivity toward activation of EPAC1 over EPAC2 in cells. Of these, 25u was found to robustly inhibit IL-6-activated signal transducer and activator of transcription 3 (STAT3) and subsequent induction of the pro-inflammatory vascular cell adhesion molecule 1 (VCAM1) cell-adhesion protein. These novel EPAC1 activators may therefore act as useful pharmacological tools for elucidation of EPAC function and promising drug leads for the treatment of relevant human diseases.

Original languageEnglish (US)
Pages (from-to)5159-5184
Number of pages26
JournalJournal of medicinal chemistry
Issue number10
StatePublished - May 28 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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