Nature Communications (Mar 2018)
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- Marcus J. G. W. Ladds,
- Ingeborg M. M. van Leeuwen,
- Catherine J. Drummond,
- Su Chu,
- Alan R. Healy,
- Gergana Popova,
- Andrés Pastor Fernández,
- Tanzina Mollick,
- Suhas Darekar,
- Saikiran K. Sedimbi,
- Marta Nekulova,
- Marijke C. C. Sachweh,
- Johanna Campbell,
- Maureen Higgins,
- Chloe Tuck,
- Mihaela Popa,
- Mireia Mayoral Safont,
- Pascal Gelebart,
- Zinayida Fandalyuk,
- Alastair M. Thompson,
- Richard Svensson,
- Anna-Lena Gustavsson,
- Lars Johansson,
- Katarina Färnegårdh,
- Ulrika Yngve,
- Aljona Saleh,
- Martin Haraldsson,
- Agathe C. A. D’Hollander,
- Marcela Franco,
- Yan Zhao,
- Maria Håkansson,
- Björn Walse,
- Karin Larsson,
- Emma M. Peat,
- Vicent Pelechano,
- John Lunec,
- Borivoj Vojtesek,
- Mar Carmena,
- William C. Earnshaw,
- Anna R. McCarthy,
- Nicholas J. Westwood,
- Marie Arsenian-Henriksson,
- David P. Lane,
- Ravi Bhatia,
- Emmet McCormack,
- Sonia Laín
Affiliations
- Marcus J. G. W. Ladds
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Ingeborg M. M. van Leeuwen
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Catherine J. Drummond
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Su Chu
- Division of Hematology and Oncology, Comprehensive Cancer Center
- Alan R. Healy
- School of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews and EaStCHEM
- Gergana Popova
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Andrés Pastor Fernández
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Tanzina Mollick
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Suhas Darekar
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Saikiran K. Sedimbi
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Marta Nekulova
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Marijke C. C. Sachweh
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Johanna Campbell
- Centre for Oncology and Molecular Medicine, University of Dundee, Ninewells Hospital and Medical School
- Maureen Higgins
- Centre for Oncology and Molecular Medicine, University of Dundee, Ninewells Hospital and Medical School
- Chloe Tuck
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Mihaela Popa
- Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen
- Mireia Mayoral Safont
- Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen
- Pascal Gelebart
- Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen
- Zinayida Fandalyuk
- Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen
- Alastair M. Thompson
- Department of Breast Surgical Oncology, MD Anderson Cancer Center, Holcombe Boulevard
- Richard Svensson
- Department of Pharmacy, Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Uppsala University
- Anna-Lena Gustavsson
- Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Lars Johansson
- Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Katarina Färnegårdh
- Drug Discovery and Development Platform, Science for Life Laboratory
- Ulrika Yngve
- Department of Medicinal Chemistry, Science for Life Laboratories, Uppsala University
- Aljona Saleh
- Department of Medicinal Chemistry, Science for Life Laboratories, Uppsala University
- Martin Haraldsson
- Drug Discovery and Development Platform, Science for Life Laboratory
- Agathe C. A. D’Hollander
- School of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews and EaStCHEM
- Marcela Franco
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Yan Zhao
- Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University
- Maria Håkansson
- SARomics Biostructures, Medicon Village
- Björn Walse
- SARomics Biostructures, Medicon Village
- Karin Larsson
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Emma M. Peat
- The Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh
- Vicent Pelechano
- SciLifeLab, Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- John Lunec
- Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University
- Borivoj Vojtesek
- RECAMO, Masaryk Memorial Cancer Institute
- Mar Carmena
- The Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh
- William C. Earnshaw
- The Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh
- Anna R. McCarthy
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Nicholas J. Westwood
- School of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews and EaStCHEM
- Marie Arsenian-Henriksson
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- David P. Lane
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- Ravi Bhatia
- Division of Hematology and Oncology, Comprehensive Cancer Center
- Emmet McCormack
- Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, Hematology Section, University of Bergen
- Sonia Laín
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
- DOI
- https://doi.org/10.1038/s41467-018-03441-3
- Journal volume & issue
-
Vol. 9,
no. 1
pp. 1 – 14
Abstract
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.