Synthesis and Biochemical Evaluation of Noncyclic Nucleotide Exchange Proteins Directly Activated by cAMP 1 (EPAC1) Regulators.
J Med Chem
; 63(10): 5159-5184, 2020 05 28.
Article
in En
| MEDLINE
| ID: mdl-32340447
ABSTRACT
Exchange proteins directly activated by cAMP (EPAC) play a central role in various biological functions, and activation of the EPAC1 protein has shown potential benefits for the treatment of various human diseases. Herein, we report the synthesis and biochemical evaluation of a series of noncyclic nucleotide EPAC1 activators. Several potent EPAC1 binders were identified including 25g, 25q, 25n, 25u, 25e, and 25f, which promote EPAC1 guanine nucleotide exchange factor activity in vitro. These agonists can also activate EPAC1 protein in cells, where they exhibit excellent selectivity toward EPAC over protein kinase A and G protein-coupled receptors. Moreover, 25e, 25f, 25n, and 25u exhibited improved selectivity toward activation of EPAC1 over EPAC2 in cells. Of these, 25u was found to robustly inhibit IL-6-activated signal transducer and activator of transcription 3 (STAT3) and subsequent induction of the pro-inflammatory vascular cell adhesion molecule 1 (VCAM1) cell-adhesion protein. These novel EPAC1 activators may therefore act as useful pharmacological tools for elucidation of EPAC function and promising drug leads for the treatment of relevant human diseases.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cyclic AMP
/
Guanine Nucleotide Exchange Factors
/
Human Umbilical Vein Endothelial Cells
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2020
Document type:
Article
Affiliation country:
United States