ArticleJournal of medicinal chemistry2013
Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase.
Article in Journal of medicinal chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 32 citations in OpenAlex.
- The translation initiation factor eIF2α regulates lipid homeostasis and metabolic aging.Aging cell · 2025Article
- 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
- Perspective: Modulating the integrated stress response to slow aging and ameliorate age-related pathology.Nature aging · 2021Article
- Oral administration of a new HRI activator as a new strategy to improve high-fat-diet-induced glucose intolerance, hepatic steatosis, and hypertriglyceridaemia through FGF21.British journal of pharmacology · 2019Article
- 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
- Therapeutic Opportunities in Eukaryotic Translation.Cold Spring Harbor perspectives in biology · 2018Review
- Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation.Scientific reports · 2018Article
- The eIF2α Kinase Heme-Regulated Inhibitor Protects the Host from Infection by Regulating Intracellular Pathogen Trafficking.Infection and immunity · 2018Article
- The eIF2-alpha kinase HRI: a potential target beyond the red blood cell.Expert opinion on therapeutic targets · 2017Review
- 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 · 2017Article
- The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma.Leukemia research · 2017Article
- ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.Science signaling · 2016Article
- Depletion of eIF2·GTP·Met-tRNAi translation initiation complex up-regulates BRCA1 expression in vitro and in vivo.Oncotarget · 2015Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Heme-regulated inhibitor kinase (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, plays critical roles in cell proliferation, differentiation, and adaptation to cytoplasmic stress. HRI is also a critical modifier of hemoglobin disorders such as β-thalassemia. We previously identified N,N'-diarylureas as potent activators of HRI suitable for studying the biology of this important kinase. To expand the repertoire of chemotypes that activate HRI, we screened a ∼1900 member N,N'-disubstituted urea library in the surrogate eIF2α phosphorylation assay, identifying N-aryl,N'-cyclohexylphenoxyurea as a promising scaffold. We validated hit compounds as a bona fide HRI activators in secondary assays and explored the contributions of substitutions on the N-aryl and N'-cyclohexylphenoxy groups to their activity by studying focused libraries of complementing analogues. We tested these N-aryl,N'-cyclohexylphenoxyureas in the surrogate eIF2α phosphorylation and cell proliferation assays, demonstrating significantly improved bioactivities and specificities. We consider these compounds to represent lead candidates for the development of potent and specific HRI activators.
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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.