Discovery of selective ATP-competitive eIF4A3 inhibitors

Bioorg Med Chem. 2017 Apr 1;25(7):2200-2209. doi: 10.1016/j.bmc.2017.02.035. Epub 2017 Feb 20.

Abstract

Eukaryotic initiation factor 4A3 (eIF4A3), an ATP-dependent RNA helicase, is a core component of exon junction complex (EJC). EJC has a variety of roles in RNA metabolism such as translation, surveillance, and localization of spliced RNA. It is worthwhile to identify selective eIF4A3 inhibitors with a view to investigating the functions of eIF4A3 and EJC further to clarify the roles of the ATPase and helicase activities in cells. Our chemical optimization of hit compound 2 culminated in the discovery of ATP-competitive eIF4A3 inhibitor 18 with submicromolar ATPase inhibitory activity and excellent selectivity over other helicases. Hence, compound 18 could be a valuable chemical probe to elucidate the detailed functions of eIF4A3 and EJC.

Keywords: ATP-competitive type inhibitors; Eukaryotic initiation factor 4A3 (eIF4A3) inhibitors; Exon junction complex (EJC); Isothermal titration calorimetry (ITC); RNA helicase; Surface plasmon resonance (SPR).

Publication types

  • Historical Article

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Chromatography, High Pressure Liquid
  • Chromatography, Thin Layer
  • DEAD-box RNA Helicases / antagonists & inhibitors*
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Eukaryotic Initiation Factor-4A / antagonists & inhibitors*
  • High-Throughput Screening Assays
  • History, Medieval
  • Proton Magnetic Resonance Spectroscopy
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Enzyme Inhibitors
  • Adenosine Triphosphate
  • Eukaryotic Initiation Factor-4A
  • EIF4A3 protein, human
  • DEAD-box RNA Helicases