Development of 1-((1,4-trans)-4-Aryloxycyclohexyl)-3-arylurea Activators of Heme-Regulated Inhibitor as Selective Activators of the Eukaryotic Initiation Factor 2 Alpha (eIF2α) Phosphorylation Arm of the Integrated Endoplasmic Reticulum Stress Response

J Med Chem. 2017 Jul 13;60(13):5392-5406. doi: 10.1021/acs.jmedchem.7b00059. Epub 2017 Jun 19.


Heme-regulated inhibitor (HRI), an eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, plays critical roles in cell proliferation, differentiation, adaptation to stress, and hemoglobin disorders. HRI phosphorylates eIF2α, which couples cellular signals, including endoplasmic reticulum (ER) stress, to translation. We previously identified 1,3-diarylureas and 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific activators of HRI that trigger the eIF2α phosphorylation arm of ER stress response as molecular probes for studying HRI biology and its potential as a druggable target. To develop drug-like cHAUs needed for in vivo studies, we undertook bioassay-guided structure-activity relationship studies and tested them in the surrogate eIF2α phosphorylation and cell proliferation assays. We further evaluated some of these cHAUs in endogenous eIF2α phosphorylation and in the expression of the transcription factor C/EBP homologous protein (CHOP) and its mRNA, demonstrating significantly improved solubility and/or potencies. These cHAUs are excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Endoplasmic Reticulum Stress / drug effects*
  • Eukaryotic Initiation Factor-2 / antagonists & inhibitors*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Humans
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / pathology
  • Mice
  • Molecular Structure
  • Phosphorylation / drug effects*
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / pathology
  • Structure-Activity Relationship
  • Urea / analysis
  • Urea / chemistry
  • Urea / pharmacology*


  • Antineoplastic Agents
  • Eukaryotic Initiation Factor-2
  • Urea