A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

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.

van Leeuwen, Ingeborg M. M. (author): Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

Drummond, Catherine J. (author): Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

Chu, Su (author): Comprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA.

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.

Popova, Gergana (author): Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

Fernandez, Andres Pastor (author): Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

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.

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.

Sedimbi, Saikiran K. (author): Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

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.

Sachweh, Marijke C. C. (author): Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

Campbell, Johanna (author): Univ Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland.

Higgins, Maureen (author): Univ Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland.

Tuck, Chloe (author): Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

Popa, Mihaela (author): Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.

Safont, Mireia Mayoral (author): Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.

Gelebart, Pascal (author): Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.

Fandalyuk, Zinayida (author): Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.

Thompson, Alastair M. (author): Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Holcombe Blvd, Houston, TX 77030 USA.

Svensson, Richard (author): Uppsala universitet,Institutionen för farmaci

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.

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.

Farnegardh, Katarina (author): Sci Life Lab, Drug Discovery & Dev Platform, Tomtebodavagen 23, SE-17121 Solna, Sweden.

Yngve, Ulrika, 1972- (author): Uppsala universitet,Preparativ läkemedelskemi

Saleh, Aljona (author): Uppsala universitet,Institutionen för farmaci

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.

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.

Franco, Marcela (author): Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

Zhao, Yan (author): Newcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England.

Hakansson, Maria (author): SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden.

Walse, Bjorn (author): SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden.

Larsson, Karin (author): Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

Peat, Emma M. (author): Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland.

Pelechano, Vicent (author): Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden.

Lunec, John (author): Newcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England.

Vojtesek, Borivoj (author): Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno 65653, Czech Republic.

Carmena, Mar (author): Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland.

Earnshaw, William C. (author): Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland.

McCarthy, Anna R. (author): Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

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.

Arsenian-Henriksson, Marie (author): Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.

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.

Bhatia, Ravi (author): Comprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA.

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.

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.
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9

Related links:: https://doi.org/10.1...; show more...; https://uu.diva-port... (primary) (Raw object); https://www.nature.c...; https://urn.kb.se/re...; https://doi.org/10.1...; http://kipublication...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

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By the author/editor: Ladds, Marcus J. ...; van Leeuwen, Ing ...; Drummond, Cather ...; Chu, Su; Healy, Alan R.; Popova, Gergana; show more...; Fernandez, Andre ...; Mollick, Tanzina; Darekar, Suhas; Sedimbi, Saikira ...; Nekulova, Marta; Sachweh, Marijke ...; Campbell, Johann ...; Higgins, Maureen; Tuck, Chloe; Popa, Mihaela; Safont, Mireia M ...; Gelebart, Pascal; Fandalyuk, Zinay ...; Thompson, Alasta ...; Svensson, Richar ...; Gustavsson, Anna ...; Johansson, Lars; Farnegardh, Kata ...; Yngve, Ulrika, 1 ...; Saleh, Aljona; Haraldsson, Mart ...; D'Hollander, Aga ...; Franco, Marcela; Zhao, Yan; Hakansson, Maria; Walse, Bjorn; Larsson, Karin; Peat, Emma M.; Pelechano, Vicen ...; Lunec, John; Vojtesek, Borivo ...; Carmena, Mar; Earnshaw, Willia ...; McCarthy, Anna R ...; Westwood, Nichol ...; Arsenian-Henriks ...; Lane, David P.; Bhatia, Ravi; McCormack, Emmet; Lain, Sonia; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmaceutical S ...

Articles in the publication: Nature Communica ...

By the university: Uppsala University; Karolinska Institutet

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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

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