Chemical genetics identify eIF2α kinase heme-regulated inhibitor as an anticancer target

Nat Chem Biol. 2011 Jul 17;7(9):610-6. doi: 10.1038/nchembio.613.


Translation initiation plays a critical role in cellular homeostasis, proliferation, differentiation and malignant transformation. Consistently, increasing the abundance of the eIF2-GTP-tRNA(i)(Met) translation initiation complex transforms normal cells and contributes to cancer initiation and the severity of some anemias. The chemical modifiers of the eIF2-GTP-tRNA(i)(Met) ternary complex are therefore invaluable tools for studying its role in the pathobiology of human disorders and for determining whether this complex can be pharmacologically targeted for therapeutic purposes. Using a cell-based assay, we identified N,N'-diarylureas as unique inhibitors of ternary complex accumulation. Direct functional-genetic and biochemical evidence demonstrated that the N,N'-diarylureas activate heme-regulated inhibitor kinase, thereby phosphorylating eIF2α and reducing the abundance of the ternary complex. Using tumor cell proliferation in vitro and tumor growth in vivo as paradigms, we demonstrate that N,N'-diarylureas are potent and specific tools for studying the role of eIF2-GTP-tRNA(i)(Met) ternary complex in the pathobiology of human disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Peptide Chain Initiation, Translational / drug effects*
  • Urea / analogs & derivatives*
  • Xenograft Model Antitumor Assays
  • eIF-2 Kinase / antagonists & inhibitors*
  • eIF-2 Kinase / chemistry
  • eIF-2 Kinase / genetics


  • Antineoplastic Agents
  • Urea
  • eIF-2 Kinase

Associated data

  • PubChem-Substance/124343390
  • PubChem-Substance/124343391
  • PubChem-Substance/124343392
  • PubChem-Substance/124343393