Mechanism of Action of an EPAC1-Selective Competitive Partial Agonist

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.