TY - JOUR
T1 - Mechanism of Action of an EPAC1-Selective Competitive Partial Agonist
AU - Shao, Hongzhao
AU - Mohamed, Hebatallah
AU - Boulton, Stephen
AU - Huang, Jinfeng
AU - Wang, Pingyuan
AU - Chen, Haiying
AU - Zhou, Jia
AU - Luchowska-Stańska, Urszula
AU - Jentsch, Nicholas G.
AU - Armstrong, Alison L.
AU - Magolan, Jakob
AU - Yarwood, Stephen
AU - Melacini, Giuseppe
N1 - Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/5/14
Y1 - 2020/5/14
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.9b02151
DO - 10.1021/acs.jmedchem.9b02151
M3 - Article
C2 - 32297742
AN - SCOPUS:85084037712
SN - 0022-2623
VL - 63
SP - 4762
EP - 4775
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 9
ER -