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A DHODH inhibitor i...
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
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- Ladds, Marcus J. G. W. (author)
- 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.
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- van Leeuwen, Ingeborg M. M. (author)
- Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Drummond, Catherine J. (author)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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show more...
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- Chu, Su (author)
- Comprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA.
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- Healy, Alan R. (author)
- 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, Gergana (author)
- Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Fernandez, Andres Pastor (author)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Mollick, Tanzina (author)
- 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.
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- Darekar, Suhas (author)
- 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.
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- Sedimbi, Saikiran K. (author)
- Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Nekulova, Marta (author)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno 65653, Czech Republic.
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- Sachweh, Marijke C. C. (author)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Campbell, Johanna (author)
- Univ Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland.
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- Higgins, Maureen (author)
- Univ Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland.
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- Tuck, Chloe (author)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Popa, Mihaela (author)
- Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.
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- Safont, Mireia Mayoral (author)
- Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.
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- Gelebart, Pascal (author)
- Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.
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- Fandalyuk, Zinayida (author)
- Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.
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- Thompson, Alastair M. (author)
- Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Holcombe Blvd, Houston, TX 77030 USA.
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- Svensson, Richard (author)
- Uppsala universitet,Institutionen för farmaci
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- Gustavsson, Anna-Lena (author)
- Karolinska 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, Lars (author)
- 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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- Farnegardh, Katarina (author)
- Sci Life Lab, Drug Discovery & Dev Platform, Tomtebodavagen 23, SE-17121 Solna, Sweden.
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- Yngve, Ulrika, 1972- (author)
- Uppsala universitet,Preparativ läkemedelskemi
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- Saleh, Aljona (author)
- Uppsala universitet,Institutionen för farmaci
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- Haraldsson, Martin (author)
- Karolinska Institutet,Sci Life Lab, Drug Discovery & Dev Platform, Tomtebodavagen 23, SE-17121 Solna, Sweden.,SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden.
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- D'Hollander, Agathe C. A. (author)
- 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, Marcela (author)
- Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Zhao, Yan (author)
- Newcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England.
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- Hakansson, Maria (author)
- SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden.
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- Walse, Bjorn (author)
- SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden.
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- Larsson, Karin (author)
- Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Peat, Emma M. (author)
- Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland.
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- Pelechano, Vicent (author)
- Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden.
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- Lunec, John (author)
- Newcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England.
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- Vojtesek, Borivoj (author)
- Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno 65653, Czech Republic.
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- Carmena, Mar (author)
- Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland.
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- Earnshaw, William C. (author)
- Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland.
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- McCarthy, Anna R. (author)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Westwood, Nicholas J. (author)
- 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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- Arsenian-Henriksson, Marie (author)
- Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.
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- Lane, David P. (author)
- 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.
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- Bhatia, Ravi (author)
- Comprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA.
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- McCormack, Emmet (author)
- Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.;Haukeland Hosp, Haematol Sect, Dept Med, Bergen, Norway.
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- Lain, Sonia (author)
- 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.
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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. (creator_code:org_t)
- 2018-03-16
- 2018
- English.
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Abstract
Subject headings
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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
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Ladds, Marcus J. ...
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van Leeuwen, Ing ...
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Drummond, Cather ...
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Chu, Su
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Healy, Alan R.
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Popova, Gergana
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show more...
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Fernandez, Andre ...
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Mollick, Tanzina
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Darekar, Suhas
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Sedimbi, Saikira ...
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Nekulova, Marta
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Sachweh, Marijke ...
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Campbell, Johann ...
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Higgins, Maureen
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Tuck, Chloe
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Popa, Mihaela
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Safont, Mireia M ...
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Gelebart, Pascal
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Fandalyuk, Zinay ...
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Thompson, Alasta ...
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Svensson, Richar ...
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Gustavsson, Anna ...
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Johansson, Lars
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Farnegardh, Kata ...
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Yngve, Ulrika, 1 ...
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Saleh, Aljona
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Haraldsson, Mart ...
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D'Hollander, Aga ...
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Franco, Marcela
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Zhao, Yan
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Hakansson, Maria
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Walse, Bjorn
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Larsson, Karin
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Peat, Emma M.
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Pelechano, Vicen ...
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Lunec, John
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Vojtesek, Borivo ...
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Carmena, Mar
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Earnshaw, Willia ...
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McCarthy, Anna R ...
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Westwood, Nichol ...
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Arsenian-Henriks ...
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Lane, David P.
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Bhatia, Ravi
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McCormack, Emmet
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Lain, Sonia
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
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Nature Communica ...
- By the university
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Uppsala University
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Karolinska Institutet