Structure-activity relationships of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs)

Zhiqing Liu, Yingmin Zhu, Haiying Chen, Pingyuan Wang, Fang C. Mei, Na Ye, Xiaodong Cheng, Jia Zhou

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators that play important roles in cancer, diabetes, heart failure, inflammations, infections, neurological disorders and other human diseases. EPAC specific modulators are urgently needed to explore EPAC's physiological function, mechanism of action and therapeutic applications. On the basis of a previously identified EPAC specific inhibitor hit ESI-09, herein we have designed and synthesized a novel series of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as potent EPAC inhibitors. Compound 31 (ZL0524) has been discovered as the most potent EPAC inhibitor with IC50 values of 3.6 µM and 1.2 µM against EPAC1 and EPAC2, respectively. Molecular docking of 31 onto an active EPAC2 structure predicts that 31 occupies the hydrophobic pocket in cAMP binding domain (CBD) and also opens up new space leading to the solvent region. These findings provide inspirations for discovering next generation of EPAC inhibitors.

Original languageEnglish (US)
Pages (from-to)5163-5166
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number23
DOIs
StatePublished - Dec 1 2017

Keywords

  • Antagonist
  • EPAC
  • Exchange proteins directly activated by cAMP
  • Molecular docking

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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