The future of EPAC-targeted therapies: agonism versus antagonism.
Pharmaceutical manipulation of cAMP levels exerts beneficial effects through the regulation of the exchange protein activated by cAMP (EPAC) and protein kinase A (PKA) signalling routes. Recent attention has turned to the specific regulation of EPAC isoforms (EPAC1 and EPAC2) as a more targeted approach to cAMP-based therapies. For example, EPAC2-selective agonists could promote insulin secretion from pancreatic β cells, whereas EPAC1-selective agonists may be useful in the treatment of vascular inflammation. By contrast, EPAC1 and EPAC2 antagonists could both be useful in the treatment of heart failure. Here we discuss whether the best way forward is to design EPAC-selective agonists or antagonists and the current strategies being used to develop isoform-selective, small-molecule regulators of EPAC1 and EPAC2 activity.
Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Euan
E
Parnell
School of Pharmacy, University of Bradford, Bradford BD7 1DP, UK.
Timothy M
TM
Palmer
Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: Stephen.Yarwood@glasgow.ac.uk.
Stephen J
SJ
Yarwood
D000818:Animals; D000242:Cyclic AMP / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D016503:Drug Delivery Systems / Q000639:trends*; D005544:Forecasting; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; D000242:Cyclic AMP
EPAC; agonism; antagonism; cAMP; diabetes; inflammation