Abstract
The cyclic 3′,5′-adenosine monophosphate (cAMP) sensor enzyme, EPAC1, is a candidate drug target in vascular endothelial cells (VECs) due to its ability to attenuate proinflammatory cytokine signalling normally associated with cardiovascular diseases (CVDs), including atherosclerosis. This is through the EPAC1-dependent induction of the suppressor of cytokine signalling gene, SOCS3, which targets inflammatory signalling proteins for ubiquitinylation and destruction by the proteosome. Given this important role for the EPAC1/SOCS3 signalling axis, we have used high throughput screening (HTS) to identify small molecule EPAC1 regulators and have recently isolated the first known non-cyclic nucleotide (NCN) EPAC1 agonist, I942. I942 therefore represents the first in class, isoform selective EPAC1 activator, with the potential to suppress pro-inflammatory cytokine signalling with a reduced risk of side effects associated with general cAMP-elevating agents that activate multiple response pathways. The development of augmented I942 analogues may therefore provide improved research tools to validate EPAC1 as a potential therapeutic target for the treatment of chronic inflammation associated with deadly CVDs.
Highlights
Cyclic adenosine monophosphate is the prototypical second messenger [1,2]; its intracellular concentration is governed by the relative expression and localization of enzymes responsible for its synthesis, adenylyl cyclases (ACs), and degradation, cyclic AMP phosphodiesterases (PDEs) [3,4,5,6,7,8]
Cyclic AMP exerts most of its effects through the activation of a range of down-stream sensors, including protein kinase A (PKA) [9,10,11,12], exchange protein directly activated by cyclic AMP proteins (EPAC) [13,14,15], Popeye domain-containing (POPDC) proteins [16,17] and cyclic nucleotide gated (CNG) ion channels [18]
Several cyclic nucleotide analogues have been developed as EPAC agonist tool compounds in recent years, some exhibiting discrimination between the two EPAC isoforms in addition to selectivity over PKA
Summary
Cyclic adenosine monophosphate (cyclic AMP) is the prototypical second messenger [1,2]; its intracellular concentration is governed by the relative expression and localization of enzymes responsible for its synthesis, adenylyl cyclases (ACs), and degradation, cyclic AMP phosphodiesterases (PDEs) [3,4,5,6,7,8]. Due to the diverse physiological responses controlled by cyclic AMP, signalling drugs have been developed to either promote cyclic AMP production, through activation of ACs [19], or inhibit its breakdown through inhibition of PDEs [7,20,21,22,23]. Both of these strategies lead to elevations in intracellular cyclic AMP, with the potential to activate all PKA, EPAC, POPDC and CNG signalling routes, depending on cell type [24]. Iannythoisf trheegasridde, ietfmfecatys baesspoocisastiebdlewtoithdegvloebloapl ccyocmlicpoAuMndPsetlhevaat tsieolne.cTtihveelfyocauctsivoafttehEisPrAevCise,wwwhiillel tahveoriedfoinrge cmoannceynotrfattheeosnidetheeffpecottsenastisaolcibaetneedfiwtsitohfgsleolbeaclticvyeclEicPAACMPacetlievvaatitoionn.foTrhtehfeoctruesaotmf tehnits orefvvieawscuwlailrl itnhfelraemfomreactioonnceanntdraetfefoorntsthteo pportoednuticael sbmenaelfil mts oolfesceulelectEivPeAECPAagCoancitsitvsattoioanchfoiervtheethtriesagtmoaeln. t of vascular inflammation and efforts to produce small molecule EPAC agonists to achieve this goal
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