Mechanism of Action of an EPAC1-Selective Competitive Partial Agonist

Hongzhao Shao, Hebatallah Mohamed, Stephen Boulton, Jinfeng Huang, Pingyuan Wang, Haiying Chen, Jia Zhou, Urszula Luchowska-Stańska, Nicholas G. Jentsch, Alison L. Armstrong, Jakob Magolan, Stephen Yarwood, Giuseppe Melacini

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The exchange protein activated by cAMP (EPAC) is a promising drug target for a wide disease range, from neurodegeneration and infections to cancer and cardiovascular conditions. A novel partial agonist of the EPAC isoform 1 (EPAC1), I942, was recently discovered, but its mechanism of action remains poorly understood. Here, we utilize NMR spectroscopy to map the I942–EPAC1 interactions at atomic resolution and propose a mechanism for I942 partial agonism. We found that I942 interacts with the phosphate binding cassette (PBC) and base binding region (BBR) of EPAC1, similar to cyclic adenosine monophosphate (cAMP). These results not only reveal the molecular basis for the I942 vs cAMP mimicry and competition, but also suggest that the partial agonism of I942 arises from its ability to stabilize an inhibition-incompetent activation intermediate distinct from both active and inactive EPAC1 states. The mechanism of action of I942 may facilitate drug design for EPAC-related diseases.
Original languageEnglish
Pages (from-to)4762-4775
Number of pages14
JournalJournal of Medicinal Chemistry
Volume63
Issue number9
Early online date16 Apr 2020
DOIs
Publication statusPublished - 14 May 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Shao, H., Mohamed, H., Boulton, S., Huang, J., Wang, P., Chen, H., Zhou, J., Luchowska-Stańska, U., Jentsch, N. G., Armstrong, A. L., Magolan, J., Yarwood, S., & Melacini, G. (2020). Mechanism of Action of an EPAC1-Selective Competitive Partial Agonist. Journal of Medicinal Chemistry, 63(9), 4762-4775. https://doi.org/10.1021/acs.jmedchem.9b02151