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

Revital Yefidoff-Freedman, Jing Fan, Lu Yan, Qingwen Zhang, Guillermo Rodrigo Reis Dos Santos, Sandeep Rana, Jacob I. Contreras, Rupam Sahoo, Debin Wan, Jun Young, Karina Luiza Dias Teixeira, Christophe Morisseau, Jose Halperin, Bruce Hammock, Amarnath Natarajan, Peimin Wang, Michael Chorev, Bertal H. Aktas

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5392-5406
Number of pages15
JournalJournal of Medicinal Chemistry
Volume60
Issue number13
DOIs
StatePublished - Jul 13 2017

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Yefidoff-Freedman, R., Fan, J., Yan, L., Zhang, Q., Dos Santos, G. R. R., Rana, S., Contreras, J. I., Sahoo, R., Wan, D., Young, J., Dias Teixeira, K. L., Morisseau, C., Halperin, J., Hammock, B., Natarajan, A., Wang, P., Chorev, M., & Aktas, B. H. (2017). 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. Journal of Medicinal Chemistry, 60(13), 5392-5406. https://doi.org/10.1021/acs.jmedchem.7b00059