ArticleJournal of medicinal chemistry2017
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.
Article in Journal of medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- Structural insights into allosteric inhibition of HRI kinase by heme binding via HDX-MS.The Biochemical journal · 2025Article
- ISR Modulators in Neurological Diseases.Current neuropharmacology · 2025Review
- Activity of the Di-Substituted Urea-Derived Compound I-17 inPathogens (Basel, Switzerland) · 2024Article
- Cellular Stress: Modulator of Regulated Cell Death.Biology · 2023Review
- Role of symmetry in 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as inhibitors of translation initiation.Bioorganic & medicinal chemistry letters · 2023Article
- Heme-regulated inhibitor: an overlooked eIF2α kinase in cancer investigations.Medical oncology (Northwood, London, England) · 2022Review
- Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells.The Journal of biological chemistry · 2022Article
- Small molecule-mediated induction of endoplasmic reticulum stress in cancer cells.RSC medicinal chemistry · 2021Article
- The integrated stress response in pulmonary disease.European respiratory review : an official journal of the European Respiratory Society · 2020Review
- The integrated stress response: From mechanism to disease.Science (New York, N.Y.) · 2020Review
- The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells.Stem cells international · 2019Review
- Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy.Bioorganic & medicinal chemistry letters · 2018Article
- HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells.Oncogene · 2018Article
- Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation.Scientific reports · 2018Article
- The eIF2-alpha kinase HRI: a potential target beyond the red blood cell.Expert opinion on therapeutic targets · 2017Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.