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Identification of A Novel Class of Benzofuran Oxoacetic Acid-Derived Ligands that Selectively Activate Cellular EPAC1.
Identification of A Novel Class of Benzofuran Oxoacetic Acid-Derived Ligands that Selectively Activate Cellular EPAC1.
- Source :
-
Cells [Cells] 2019 Nov 12; Vol. 8 (11). Date of Electronic Publication: 2019 Nov 12. - Publication Year :
- 2019
-
Abstract
- Cyclic AMP promotes EPAC1 and EPAC2 activation through direct binding to a specific cyclic nucleotide-binding domain (CNBD) within each protein, leading to activation of Rap GTPases, which control multiple cell responses, including cell proliferation, adhesion, morphology, exocytosis, and gene expression. As a result, it has become apparent that directed activation of EPAC1 and EPAC2 with synthetic agonists may also be useful for the future treatment of diabetes and cardiovascular diseases. To identify new EPAC agonists we have developed a fluorescent-based, ultra-high-throughput screening (uHTS) assay that measures the displacement of binding of the fluorescent cAMP analogue, 8-NBD-cAMP to the EPAC1 CNBD. Triage of the output of an approximately 350,000 compound screens using this assay identified a benzofuran oxaloacetic acid EPAC1 binder (SY000) that displayed moderate potency using orthogonal assays (competition binding and microscale thermophoresis). We next generated a limited library of 91 analogues of SY000 and identified SY009, with modifications to the benzofuran ring associated with a 10-fold increase in potency towards EPAC1 over SY000 in binding assays. In vitro EPAC1 activity assays confirmed the agonist potential of these molecules in comparison with the known EPAC1 non-cyclic nucleotide (NCN) partial agonist, I942. Rap1 GTPase activation assays further demonstrated that SY009 selectively activates EPAC1 over EPAC2 in cells. SY009 therefore represents a novel class of NCN EPAC1 activators that selectively activate EPAC1 in cellulae.
- Subjects :
- Acetates chemistry
Binding Sites
Cell Line
Cyclic AMP metabolism
Guanine Nucleotide Exchange Factors agonists
Guanine Nucleotide Exchange Factors genetics
High-Throughput Screening Assays
Humans
Ligands
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Acetates pharmacology
Benzofurans chemistry
Guanine Nucleotide Exchange Factors chemistry
Guanine Nucleotide Exchange Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2073-4409
- Volume :
- 8
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cells
- Publication Type :
- Academic Journal
- Accession number :
- 31726720
- Full Text :
- https://doi.org/10.3390/cells8111425