Identification and characterization of small molecules as potent and specific EPAC2 antagonists

Haijun Chen, Tamara Tsalkova, Oleg G. Chepurny, Fang C. Mei, George G. Holz, Xiaodong Cheng, Jia Zhou

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 IC50 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.

Original languageEnglish (US)
Pages (from-to)952-962
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number3
DOIs
StatePublished - Feb 14 2013

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Physiological Phenomena
Second Messenger Systems
Inhibitory Concentration 50
Protein Isoforms
Pharmacology
ESI-05

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Identification and characterization of small molecules as potent and specific EPAC2 antagonists. / Chen, Haijun; Tsalkova, Tamara; Chepurny, Oleg G.; Mei, Fang C.; Holz, George G.; Cheng, Xiaodong; Zhou, Jia.

In: Journal of Medicinal Chemistry, Vol. 56, No. 3, 14.02.2013, p. 952-962.

Research output: Contribution to journalArticle

Chen, Haijun ; Tsalkova, Tamara ; Chepurny, Oleg G. ; Mei, Fang C. ; Holz, George G. ; Cheng, Xiaodong ; Zhou, Jia. / Identification and characterization of small molecules as potent and specific EPAC2 antagonists. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 3. pp. 952-962.
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AU - Holz, George G.

AU - Cheng, Xiaodong

AU - Zhou, Jia

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