Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase

J Med Chem. 2013 Dec 12;56(23):9457-70. doi: 10.1021/jm400793v. Epub 2013 Nov 27.


Heme-regulated inhibitor kinase (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, plays critical roles in cell proliferation, differentiation, and adaptation to cytoplasmic stress. HRI is also a critical modifier of hemoglobin disorders such as β-thalassemia. We previously identified N,N'-diarylureas as potent activators of HRI suitable for studying the biology of this important kinase. To expand the repertoire of chemotypes that activate HRI, we screened a ∼1900 member N,N'-disubstituted urea library in the surrogate eIF2α phosphorylation assay, identifying N-aryl,N'-cyclohexylphenoxyurea as a promising scaffold. We validated hit compounds as a bona fide HRI activators in secondary assays and explored the contributions of substitutions on the N-aryl and N'-cyclohexylphenoxy groups to their activity by studying focused libraries of complementing analogues. We tested these N-aryl,N'-cyclohexylphenoxyureas in the surrogate eIF2α phosphorylation and cell proliferation assays, demonstrating significantly improved bioactivities and specificities. We consider these compounds to represent lead candidates for the development of potent and specific HRI activators.

Publication types

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

MeSH terms

  • Cell Line
  • Cell Proliferation / drug effects
  • Enzyme Activators / chemical synthesis
  • Enzyme Activators / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • MCF-7 Cells
  • Structure-Activity Relationship
  • Urea / analogs & derivatives*
  • eIF-2 Kinase / metabolism*


  • Enzyme Activators
  • Urea
  • eIF-2 Kinase