Given the above findings, we propose that the derivatives of I942 with enhanced EPAC1 activation should be pursued by replacement of the naphthyl group with moieties designed to engage in hydrogen bonding interactions with K353 (Figure ). Additionally, ligand modifications to engage G269 in addition to residues 279-281 should allow for greater PBC rearrangement upon ligand binding and greater stabilisation of EPAC1's active state.