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A DHODH inhibitor i...
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Ladds, Marcus J. G. W.Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden.
(author)
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- Article/chapterEnglish2018
Publisher, publication year, extent ...
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2018-03-16
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Springer Science and Business Media LLC,2018
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-351427
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-351427URI
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https://doi.org/10.1038/s41467-018-03441-3DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:137843272URI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Correction in: Nature Communications volume 14, Article number: 5019 (2023)DOI: 10.1038/s41467-023-40764-2
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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.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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van Leeuwen, Ingeborg M. M.Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
(author)
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Drummond, Catherine J.Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
(author)
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Chu, SuComprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA.
(author)
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Healy, Alan R.Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland.;Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland.;EaStCHEM, St Andrews KY16 9ST, Fife, Scotland.
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Popova, GerganaKarolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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Fernandez, Andres PastorKarolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
(author)
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Mollick, TanzinaKarolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden.
(author)
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Darekar, SuhasKarolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden.
(author)
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Sedimbi, Saikiran K.Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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Nekulova, MartaKarolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno 65653, Czech Republic.
(author)
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Sachweh, Marijke C. C.Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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Campbell, JohannaUniv Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland.
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Higgins, MaureenUniv Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland.
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Tuck, ChloeKarolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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Popa, MihaelaUniv Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.
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Safont, Mireia MayoralUniv Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.
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Gelebart, PascalUniv Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.
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Fandalyuk, ZinayidaUniv Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.
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Thompson, Alastair M.Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Holcombe Blvd, Houston, TX 77030 USA.
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Svensson, RichardUppsala universitet,Institutionen för farmaci(Swepub:uu)ricsv977
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Gustavsson, Anna-LenaKarolinska Institutet,Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17121 Stockholm, Sweden.
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Johansson, LarsKarolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17121 Stockholm, Sweden.
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Farnegardh, KatarinaSci Life Lab, Drug Discovery & Dev Platform, Tomtebodavagen 23, SE-17121 Solna, Sweden.
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Yngve, Ulrika,1972-Uppsala universitet,Preparativ läkemedelskemi(Swepub:uu)ulriyngv
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Saleh, AljonaUppsala universitet,Institutionen för farmaci(Swepub:uu)aljsa108
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Haraldsson, MartinKarolinska Institutet,Sci Life Lab, Drug Discovery & Dev Platform, Tomtebodavagen 23, SE-17121 Solna, Sweden.,SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden.
(author)
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D'Hollander, Agathe C. A.Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland.;Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland.;EaStCHEM, St Andrews KY16 9ST, Fife, Scotland.
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Franco, MarcelaKarolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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Zhao, YanNewcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England.
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Hakansson, MariaSARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden.
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Walse, BjornSARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden.
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Larsson, KarinKarolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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Peat, Emma M.Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland.
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Pelechano, VicentKarolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden.
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Lunec, JohnNewcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England.
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Vojtesek, BorivojMasaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno 65653, Czech Republic.
(author)
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Carmena, MarUniv Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland.
(author)
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Earnshaw, William C.Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland.
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McCarthy, Anna R.Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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Westwood, Nicholas J.Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland.;Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland.;EaStCHEM, St Andrews KY16 9ST, Fife, Scotland.
(author)
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Arsenian-Henriksson, MarieKarolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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Lane, David P.Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden.
(author)
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Bhatia, RaviComprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA.
(author)
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McCormack, EmmetUniv Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.;Haukeland Hosp, Haematol Sect, Dept Med, Bergen, Norway.
(author)
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Lain, SoniaKarolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden.
(author)
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Karolinska InstitutetKarolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden.
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In:Nature Communications: Springer Science and Business Media LLC92041-1723
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