1. 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
- Author
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Rupam Sahoo, Karina Luiza Dias Teixeira, Debin Wan, Lu Yan, Peimin Wang, Michael Chorev, Bruce D. Hammock, Bertal H. Aktas, Christophe Morisseau, Jacob I. Contreras, Amarnath Natarajan, Revital Yefidoff-Freedman, Guillermo Rodrigo Reis dos Santos, Sandeep Rana, Jun Young, Jing Fan, Jose A. Halperin, and Qingwen Zhang
- Subjects
0301 basic medicine ,Skin Neoplasms ,Eukaryotic Initiation Factor-2 ,Melanoma, Experimental ,Antineoplastic Agents ,Article ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Urea ,Phosphorylation ,Transcription factor ,Cell Proliferation ,Messenger RNA ,Dose-Response Relationship, Drug ,Molecular Structure ,Kinase ,Cell growth ,Chemistry ,Endoplasmic reticulum ,Translation (biology) ,Endoplasmic Reticulum Stress ,030104 developmental biology ,Biochemistry ,Molecular Medicine ,Drug Screening Assays, Antitumor - 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.
- Published
- 2017
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