ArticleNature communications2018
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.
Erratum issuedOpen access · goldAbstract read
In one paragraph
Article in Nature communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 52 papers.
0numbers the graph read from it
0cells of the map it votes in
52citing papers in PubMed
4.3field-weighted citation impact, top 5% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
52 citing papers in PubMed, 90 citations in OpenAlex.
- DHODH is the key target of the KDM4 inhibitor QC6352 in glioblastoma stem cells.Nature chemical biology · 2026Article
- Disrupting Notch signalling by a small molecule inhibiting dihydroorotate dehydrogenase activity.Scientific reports · 2026Article
- Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.Molecular & cellular proteomics : MCP · 2026Article
- Pan-cancer analysis of pyrimidine metabolism reveals signaling pathways connections with chemoresistance role.British journal of cancer · 2026Article
- TP53-dependent antitumor effects of DHODH Inhibition in nasopharyngeal carcinoma.Discover oncology · 2025Article
- Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.Molecular biomedicine · 2025Article
- Comprehensive Identification and Mechanistic Evaluation of Novel DHODH Inhibitors as Potent Broad-Spectrum Antiviral Agents.Pharmaceuticals (Basel, Switzerland) · 2025Article
- The DHODH inhibitor teriflunomide impedes cell proliferation and enhances chemosensitivity to daunorubicin (DNR) in T-cell acute lymphoblastic leukemia.Annals of hematology · 2024Article
- Mechanisms of S-phase arrest and mitochondrial dysfunction in complex III by DHODH inhibitors in tumorigenic TNBC cells.Histochemistry and cell biology · 2024Article
- Unlocking the Gateway: The Spatio-Temporal Dynamics of the p53 Family Driven by the Nuclear Pores and Its Implication for the Therapeutic Approach in Cancer.International journal of molecular sciences · 2024Review
- Bioinformatics analysis and experimental verification of the cancer-promoting effect of DHODH in clear cell renal cell carcinoma.Scientific reports · 2024Article
- Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia.JCI insight · 2024Article
- Small-molecule agents for cancer immunotherapy.Acta pharmaceutica Sinica. B · 2024Review
- Retinoblastoma vulnerability to combinedHeliyon · 2024Article
- Green Approach Toward Triazole Forming Reactions for Developing Anticancer Drugs.Current organic synthesis · 2024Review
- Dihydroorotate dehydrogenase promotes cell proliferation and suppresses cell death in esophageal squamous cell carcinoma and colorectal carcinoma.Translational cancer research · 2023Article
- Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus.Cold Spring Harbor perspectives in medicine · 2023Article
- Dihydroorotate dehydrogenase regulates ferroptosis in neurons after spinal cord injury via the P53-ALOX15 signaling pathway.CNS neuroscience & therapeutics · 2023Article
- Proof-of-principle studies on a strategy to enhance nucleotide imbalance specifically in cancer cells.Cell death discovery · 2022Article
- Article
Corrections and comments
- Erratum issued
- Erratum issued
Authors and funding
46 authors at 12 institutions in 5 countries.
Marcus J G W LaddsDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Ingeborg M M van LeeuwenDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Catherine J DrummondDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Su ChuDivision of Hematology and Oncology, Comprehensive Cancer Center, 1720 2nd Avenue South, NP2540, Birmingham, AL, 35294-3300, USA.
Alan R HealySchool of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews and EaStCHEM, St. Andrews, Fife, Scotland, KY16 9ST, UK.
Gergana PopovaDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Andrés Pastor FernándezDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Tanzina MollickDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Suhas DarekarDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Saikiran K SedimbiDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Marta NekulovaDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Marijke C C SachwehDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Johanna CampbellCentre for Oncology and Molecular Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Tayside, DD1 9SY, UK.
Maureen HigginsCentre for Oncology and Molecular Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Tayside, DD1 9SY, UK.
Chloe TuckDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Mihaela PopaCentre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen, 5021, Bergen, Norway.
Mireia Mayoral SafontCentre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen, 5021, Bergen, Norway.
Pascal GelebartCentre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen, 5021, Bergen, Norway.
Zinayida FandalyukCentre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen, 5021, Bergen, Norway.
Alastair M ThompsonDepartment of Breast Surgical Oncology, MD Anderson Cancer Center, Holcombe Boulevard, Houston, 77030, USA.
Richard SvenssonDepartment of Pharmacy, Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Uppsala University, SE-752 37, Uppsala, Sweden.
Anna-Lena GustavssonChemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 21, Stockholm, Sweden.
Lars JohanssonChemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 21, Stockholm, Sweden.
Katarina FärnegårdhDrug Discovery and Development Platform, Science for Life Laboratory, Tomtebodavägen 23, SE-171 21, Solna, Sweden.
Ulrika YngveDepartment of Medicinal Chemistry, Science for Life Laboratories, Uppsala University, SE-751 23, Uppsala, Sweden.
Aljona SalehDepartment of Medicinal Chemistry, Science for Life Laboratories, Uppsala University, SE-751 23, Uppsala, Sweden.
Martin HaraldssonDrug Discovery and Development Platform, Science for Life Laboratory, Tomtebodavägen 23, SE-171 21, Solna, Sweden.
Agathe C A D'HollanderSchool of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews and EaStCHEM, St. Andrews, Fife, Scotland, KY16 9ST, UK.
Marcela FrancoDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Yan ZhaoNewcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle, NE1 7RU, UK.
Maria HåkanssonSARomics Biostructures, Medicon Village, SE-223 81, Lund, Sweden.
Björn WalseSARomics Biostructures, Medicon Village, SE-223 81, Lund, Sweden.
Karin LarssonDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-6403-2736
Emma M PeatThe Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, EH9 3JR, UK.
Vicent PelechanoSciLifeLab, Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Tomtebodavägen 23, SE-171 21, Stockholm, Sweden.
John LunecNewcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle, NE1 7RU, UK.
Borivoj VojtesekRECAMO, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 65653, Brno, Czech Republic.
Mar CarmenaThe Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, EH9 3JR, UK.ORCID http://orcid.org/0000-0002-2352-1066
William C EarnshawThe Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, EH9 3JR, UK.
Anna R McCarthyDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Nicholas J WestwoodSchool of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews and EaStCHEM, St. Andrews, Fife, Scotland, KY16 9ST, UK.ORCID http://orcid.org/0000-0003-0630-0138
Marie Arsenian-HenrikssonDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
David P LaneDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Ravi BhatiaDivision of Hematology and Oncology, Comprehensive Cancer Center, 1720 2nd Avenue South, NP2540, Birmingham, AL, 35294-3300, USA.
Emmet McCormackCentre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen, 5021, Bergen, Norway.
Sonia LaínDepartment of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77, Stockholm, Sweden. sonia.lain@ki.se.
Karolinska Institutet · SEScience for Life Laboratory · SEUniversity of Bergen · NOUniversity of St Andrews · GBUppsala University · SEWellcome Centre for Cell Biology · GBMedicon Village · SENewcastle University · GBUniversity of Dundee · GBHaukeland University Hospital · NOMasaryk Memorial Cancer Institute · CZThe University of Texas MD Anderson Cancer Center · US
Funding
Resistance of CML stem cells to STI571 (Gleevec)R01CA095684 · NCI · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI BHATIA, RAVI · 2003 to 2017
$4.6MNCI NIH HHS R01 CA095684Wellcome Trust
Abstract
The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
Indexed as
Antineoplastic AgentsCell CycleCell Line, TumorCell ProliferationDihydroorotate DehydrogenaseEnzyme InhibitorsHumansIndazolesNeoplasmsOxidoreductases Acting on CH-CH Group DonorsProteolysisTumor Suppressor Protein p53Antineoplastic AgentsDihydroorotate DehydrogenaseEnzyme InhibitorsIndazolesOxidoreductases Acting on CH-CH Group DonorsTumor Suppressor Protein p53
Identifiers
What OpenQuestion holds
Textmetadata
LicenceCC BY
Read underepoch 390
Registered trials
None linked
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.