Marion Laudette1,2, Antonio Coluccia3, Yannis Sainte-Marie1,2, Andrea Solari1,2, Loubina Fazal1,2, Pierre Sicard4, Romano Silvestri3, Jeanne Mialet-Perez1,2, Sandrine Pons5, Bijan Ghaleh5, Jean-Paul Blondeau6, Frank Lezoualc'h1,2. 1. INSERM UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Pouhlès, Toulouse, France. 2. Université de Toulouse-Paul Sabatier, Toulouse, France. 3. Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory Affiliated to Instituto Pasteur Italia-Fondazione Cenci Bolognetti, Roma, Italy. 4. INSERM, CNRS, Université de Montpellier, PHYMEDEXP, IPAM, Montpellier, France. 5. INSERM, U955, Equipe 03, F-94000 Créteil, France. 6. Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry Cedex, France.
Abstract
AIMS: Recent studies reported that cAMP-binding protein Epac1-deficient mice were protected against various forms of cardiac stress, suggesting that pharmacological inhibition of Epac1 could be beneficial for the treatment of cardiac diseases. To test this assumption, we characterized an Epac1-selective inhibitory compound and investigated its potential cardioprotective properties. METHODS AND RESULTS: We used the Epac1-BRET (bioluminescence resonance energy transfer) for searching for non-cyclic nucleotide Epac1 modulators. A thieno[2,3-b]pyridine derivative, designated as AM-001 was identified as a non-competitive inhibitor of Epac1. AM-001 has no antagonist effect on Epac2 or protein kinase A activity. This small molecule prevents the activation of the Epac1 downstream effector Rap1 in cultured cells, in response to the Epac1 preferential agonist, 8-CPT-AM. In addition, we found that AM-001 inhibited Epac1-dependent deleterious effects such as cardiomyocyte hypertrophy and death. Importantly, AM-001-mediated inhibition of Epac1 reduces infarct size after mouse myocardial ischaemia/reperfusion injury. Finally, AM-001 attenuates cardiac hypertrophy, inflammation and fibrosis, and improves cardiac function during chronic β-adrenergic receptor activation with isoprenaline (ISO) in mice. At the molecular level, ISO increased Epac1-G protein-coupled receptor kinase 5 (GRK5) interaction and induced GRK5 nuclear import and histone deacetylase type 5 (HDAC5) nuclear export to promote the activity of the prohypertrophic transcription factor, myocyte enhancer factor 2 (MEF2). Inversely, AM-001 prevented the non-canonical action of GRK5 on HDAC5 cytoplasmic shuttle to down-regulate MEF2 transcriptional activity. CONCLUSION: Our study represents a 'proof-of-concept' for the therapeutic effectiveness of inhibiting Epac1 activity in cardiac disease using small-molecule pharmacotherapy. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Recent studies reported that cAMP-binding protein Epac1-deficient mice were protected against various forms of cardiac stress, suggesting that pharmacological inhibition of Epac1 could be beneficial for the treatment of cardiac diseases. To test this assumption, we characterized an Epac1-selective inhibitory compound and investigated its potential cardioprotective properties. METHODS AND RESULTS: We used the Epac1-BRET (bioluminescence resonance energy transfer) for searching for non-cyclic nucleotideEpac1 modulators. A thieno[2,3-b]pyridine derivative, designated as AM-001 was identified as a non-competitive inhibitor of Epac1. AM-001 has no antagonist effect on Epac2 or protein kinase A activity. This small molecule prevents the activation of the Epac1 downstream effector Rap1 in cultured cells, in response to the Epac1 preferential agonist, 8-CPT-AM. In addition, we found that AM-001 inhibited Epac1-dependent deleterious effects such as cardiomyocyte hypertrophy and death. Importantly, AM-001-mediated inhibition of Epac1 reduces infarct size after mouse myocardial ischaemia/reperfusion injury. Finally, AM-001 attenuates cardiac hypertrophy, inflammation and fibrosis, and improves cardiac function during chronic β-adrenergic receptor activation with isoprenaline (ISO) in mice. At the molecular level, ISO increased Epac1-G protein-coupled receptor kinase 5 (GRK5) interaction and induced GRK5 nuclear import and histone deacetylase type 5 (HDAC5) nuclear export to promote the activity of the prohypertrophic transcription factor, myocyte enhancer factor 2 (MEF2). Inversely, AM-001 prevented the non-canonical action of GRK5 on HDAC5 cytoplasmic shuttle to down-regulate MEF2 transcriptional activity. CONCLUSION: Our study represents a 'proof-of-concept' for the therapeutic effectiveness of inhibiting Epac1 activity in cardiac disease using small-molecule pharmacotherapy. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Mohit M Hulsurkar; Satadru K Lahiri; Jason Karch; Meng C Wang; Xander H T Wehrens Journal: Expert Opin Ther Targets Date: 2022-04-25 Impact factor: 6.797
Authors: Marianna Bufano; Marion Laudette; Jean-Paul Blondeau; Frank Lezoualc'h; Marianna Nalli; Romano Silvestri; Andrea Brancale; Antonio Coluccia Journal: J Comput Aided Mol Des Date: 2020-07-22 Impact factor: 3.686