Initial efforts to drug EPAC1 were focused on design of cAMP analogues, such as 8-pCPT-2'-O-Me-cAMP, an EPAC1-selective agonist (Figure ). However, these suffered from poor membrane permeability due to the presence of a negatively-charged phosphate group. To overcome this liability, the negative charge was masked with an acetoxymethyl ester, which is hydrolysed by cytosolic esterase enzymes to return the active agent. Whilst this improved bioavailability, some cAMP analogues were also associated with off-target effects, particularly non-selective activation of EPAC2 and PKA. These side effects have shifted the focus of activating EPAC1 to non-cAMP-like small molecules, leading to the development of I942 (Figure and), a selective partial EPAC1 agonist. I942 was identified in a high-throughput screen (HTS) of lead-like small molecules, using a competitive displacement assay of fluorescent cAMP analogue 8-NBD-cAMP. I942 induces partial activation of EPAC1 in cells. I942 is also more drug-like compared to cAMP analogues, and provides a more suitable scaffold for further lead optimisation towards a full selective activator. NMR studies have suggested that while I942 binds to the same site as cAMP, the partial activation of EPAC1 arises from the stabilization of an intermediate state, rather than the active conformation of EPAC1. In this intermediate state, the PBC has adopted an "in", or active-like, conformation, but the hinge in the cNBD has not yet shifted and remains in the "out", or inactive-like" conformation. While the NMR work done on EPAC1-I942 has provided evidence for the intermediate state stabilization to explain the partial activation observed, the data on I942 is still sparse and limited by the experimental techniques employed. Due to poor stability of full length EPAC1, only the more stable isolated EPAC1-cNBD was used for the original HTS screen that identified I942. When the full length protein was used in the activation assay, cAMP affinity was found to be 10-fold higher than seen previously with just the cNBD, whereas I942 affinity to both structures was very similar. Additionally, the work by Shao et al. also used only EPAC1-cNBD (residues 149-318), which precluded assessment of the significance of ligand interactions with the catalytic region (such as K353 shown in Figure and).