The future of EPAC-targeted therapies: Agonism versus antagonism

Euan Parnell; Timothy M. Palmer; Stephen J. Yarwood

doi:10.1016/j.tips.2015.02.003

The future of EPAC-targeted therapies: Agonism versus antagonism

Euan Parnell, Timothy M. Palmer, Stephen J. Yarwood^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

61 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	203-214
Number of pages	12
Journal	Trends in Pharmacological Sciences
Volume	36
Issue number	4
DOIs	https://doi.org/10.1016/j.tips.2015.02.003
State	Published - Apr 1 2015
Externally published	Yes

Keywords

EPAC
agonism
antagonism
cAMP
diabetes
inflammation

ASJC Scopus subject areas

Toxicology
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.tips.2015.02.003

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title = "The future of EPAC-targeted therapies: Agonism versus antagonism",

abstract = "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.",

keywords = "EPAC, agonism, antagonism, cAMP, diabetes, inflammation",

author = "Euan Parnell and Palmer, {Timothy M.} and Yarwood, {Stephen J.}",

note = "Funding Information: Work in S.J.Y. and T.M.P.{\textquoteright}s laboratories was funded by project grants from the British Heart Foundation (BHF) (PG/05/026, PG/08/125/26415, PG/10/026/28303) and the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/D015324/1). E.P. was supported by a doctoral training studentship from the BBSRC Doctoral Training Programme in Biochemistry and Molecular Biology at the University of Glasgow (BB/F016735/1). Publisher Copyright: {\textcopyright} 2015 The Authors Published by Elsevier Ltd.",

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doi = "10.1016/j.tips.2015.02.003",

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AU - Parnell, Euan

AU - Palmer, Timothy M.

AU - Yarwood, Stephen J.

N1 - Funding Information: Work in S.J.Y. and T.M.P.’s laboratories was funded by project grants from the British Heart Foundation (BHF) (PG/05/026, PG/08/125/26415, PG/10/026/28303) and the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/D015324/1). E.P. was supported by a doctoral training studentship from the BBSRC Doctoral Training Programme in Biochemistry and Molecular Biology at the University of Glasgow (BB/F016735/1). Publisher Copyright: © 2015 The Authors Published by Elsevier Ltd.

PY - 2015/4/1

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N2 - 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.

AB - 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.

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KW - inflammation

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The future of EPAC-targeted therapies: Agonism versus antagonism

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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