Synthesis and Biochemical Evaluation of Non-Cyclic Nucleotide Exchange Protein Directly Activated by cAMP 1 (EPAC1) Regulators.

EPAC plays 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 non-cyclic nucleotide EPAC1 activators. Several potent EPAC1 binders were identified including 25g, 25q, 25n, 25u, 25e and 25f, which promote EPAC1 GEF activity in vitro. These agonists can also activate EPAC1 protein in cells, where they exhibit excellent selectivity towards EPAC over PKA and GPCRs. Moreover, 25e, 25f, 25n and 25u exhibited improved selectivity towards activation of EPAC1 over EPAC2 in cells. Of these, 25u was found to robustly inhibit IL-6-activated STAT3 and subsequent induction of the pro-inflammatory VCAM1 cell adhesion protein. These novel EPAC1 activators may therefore act as useful pharmacological tools for elucidation of EPAC function as well as promising drug leads for the treatment of relevant human diseases.

• Publication year

  2020

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2020-04-28

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.jmedchem.9b02094PMID 32340447
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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