Identification and characterisation of novel small-molecule activators of EPAC1
Abstract
EPAC1 is a cyclic AMP sensor protein involved in a multitude of physiological and
pathophysiological processes in the human body and has been recognised as an attractive
target for pharmacological regulation. Activation of EPAC1 protein was reported to
suppress chronic vascular inflammation, making it a potential therapeutic strategy for the
prevention and treatment of cardiovascular disease. While literature describes a range of
EPAC1 inhibitors, no selective small-molecule activators of this protein have been
reported until the 2017 discovery of the N-acylsulphonamide derivative, I942, in the
Yarwood laboratory. The presented study follows up on this finding and aims to identify
novel EPAC1 ligands with agonist properties. A two-phase screening approach was
employed to detect EPAC1-binding compounds with potential agonist component in a
carefully designed library of I942 analogues. Hits from the screen were further analysed
in terms of activity, EPAC1-selectivity, and cytotoxicity, using in vitro biochemical
assays and cell-based tests, alongside another new class of EPAC1 activators identified
in the Yarwood laboratory, benzofuran oxoacetic acid derivatives. In addition to that, the
mechanism of ligand-mediated cytotoxicity was investigated. Three novel, selective,
small-molecule EPAC1-regulators with agonist properties and good safety profiles were
identified, which can serve as promising lead compounds for drug development.