Dr Graeme Barker

Project Title: Exploring a New Class of EPAC1 Agonists: Towards Novel Treatments for Atherosclerosis

Atherosclerosis is a condition caused by narrowing of arteries, leading on to heart attack, stroke, and other cardiovascular conditions conditions. It remains irreversible with current treatments and is the leading cause of death in the world. Our project targets the enzyme EPAC1, known to be involved in the development of atherosclerosis. Under normal conditions EPAC1 is activated by a small molecule, cAMP, which “switches on” the enzyme. While the involvement of EPAC1 in atherosclerosis is known, its exact role in living cells is not fully understood and it has not previously been targeted for drug development for a simple reason: cAMP also activates the enzymes EPAC2 and PKA. Thus, administering cAMP or a related chemical to a patient would produce unwanted side effects. In collaboration with biology colleagues, we have recently identified the first selective activator of EPAC1, called I942. During this project, my group will build on this discovery to design and synthesize analogues of I942 to improve the activity of these new molecules, use them to fully identify the role of EPAC1, and progress towards a viable new drug for atherosclerosis treatment which does not exhibit side effects from unwanted activation of EPAC2 or PKA.