Development of Small Molecule EPAC1 Activity Modulators

EPAC1 is a cellular signalling enzyme known to play a key role in a variety of conditions including atherosclerosis, insulin resistance and some cancers. Despite this promising outlook as a drug development target, EPAC1 has received little previous attention from medicinal chemists, and the precise role of EPAC1 in cellular signalling cascades is yet to be determined. The reason for this discrepancy is simple: the naturally occurring EPAC1 ligand cAMP also activates EPAC2 and PKA. Thus, cAMP and its analogues exhibit significant off target effects. Using a high-throughput screening strategy, we have recently identified the first non-cyclic nucleotide agonist for EPAC1, I942. The aim of this project is to expand the I942 series and conduct a full structure-activity relationship (SAR) study with the aim of developing selective EPAC1 agonists and antagonists suitable for in vivo use. In collaboration with Prof. David Adams, we will generate likely docking models of new analogues into EPAC1 model structures. These will then be assessed and used to determine promising new structures for synthesis. This work, and the synthesis of compound libraries will take place in Dr Barker’s group. New EPAC1 ligands will then be assessed in Dr Yarwood’s group for biological activity.

The Institute of Chemical Sciences (ICS) is an excellent environment for PhD research, with a thriving community of academics, post-doctoral and PhD researchers spread across three sections: Molecular Chemistry, Materials Chemistry, and Dynamics and Structure. ICS also has many links to the other research institutes within the overall umbrella of the School of Engineering and Physical Sciences, providing a strong interdisciplinary theme to our research. Heriot-Watt University occupies an attractive campus site on the outskirts of Edinburgh, with excellent public transport links to the centre of one of the Europe’s most exciting cities.