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

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.