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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Yefidoff-Freedman, Revital, Fan, Jing, Yan, Lu, Zhang, Qingwen, dos Santos, Guillermo Rodrigo Reis, Rana, Sandeep, Contreras, Jacob I, Sahoo, Rupam, Wan, Debin, Young, Jun, Teixeira, Karina Luiza Dias, Morisseau, Christophe, Halperin, Jose, Hammock, Bruce, Natarajan, Amarnath, Wang, Peimin, Chorev, Michael, and Aktas, Bertal H
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Genetics ,1.1 Normal biological development and functioning ,Generic health relevance ,Animals ,Antineoplastic Agents ,Cell Line ,Tumor ,Cell Proliferation ,Dose-Response Relationship ,Drug ,Drug Screening Assays ,Antitumor ,Endoplasmic Reticulum Stress ,Eukaryotic Initiation Factor-2 ,Humans ,Melanoma ,Experimental ,Mice ,Molecular Structure ,Phosphorylation ,Skin Neoplasms ,Structure-Activity Relationship ,Urea ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Medicinal & Biomolecular Chemistry ,Pharmacology and pharmaceutical sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - 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