title: Identification and characterization of small molecules as potent and specific EPAC2 antagonists.
abstract: EPAC1 and EPAC2, two isoforms of exchange proteins directly activated by cAMP (EPAC), respond to the second messenger cAMP and regulate a wide variety of intracellular processes under physiological and pathophysiological circumstances. Herein, we report the chemical design, synthesis, and pharmacological characterization of three different scaffolds (diarylsulfones, N,N-diarylamines, and arylsulfonamides) as highly potent and selective antagonists of EPAC2. Several selective EPAC2 antagonists have been identified including 20i (HJC0350), which has an apparent IC(50) of 0.3 μM for competing with 8-NBD-cAMP binding of EPAC2 and is about 133-fold more potent than cAMP. Compounds 1 (ESI-05), 14c (HJC0338), and 20i, selected from each series, have exhibited no inhibition of EPAC1-mediated Rap1-GDP exchange activity at 25 μM, indicating that they are EPAC2-specific antagonists. Moreover, live-cell imaging studies using EPAC1, EPAC2, or PKA FRET sensor also demonstrate that 20i functions as an EPAC2 specific antagonist.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Chen
authors.forename: Tamara
authors.initials: T
authors.lastname: Tsalkova
authors.forename: Oleg G
authors.initials: OG
authors.lastname: Chepurny
authors.forename: Fang C
authors.initials: FC
authors.lastname: Mei
authors.forename: George G
authors.initials: GG
authors.lastname: Holz
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
mesh_terms: D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D054852:Small Molecule Libraries; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C442864:RAPGEF4 protein, human; D054852:Small Molecule Libraries