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

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5163-5166. doi: 10.1016/j.bmcl.2017.10.056. Epub 2017 Oct 25.

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.

Keywords: Antagonist; EPAC; Exchange proteins directly activated by cAMP; Molecular docking.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Cyanides / chemistry*
  • Cyanides / metabolism
  • Cyclic AMP / chemistry
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Cyanides
  • Guanine Nucleotide Exchange Factors
  • RAPGEF3 protein, human
  • RAPGEF4 protein, human
  • Cyclic AMP