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1. Corrigendum: MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Author

Helge, Gad, Tobias, Koolmeister, Ann-Sofie, Jemth, Saeed, Eshtad, Sylvain A, Jacques, Cecilia E, Ström, Linda M, Svensson, Niklas, Schultz, Thomas, Lundbäck, Berglind Osk, Einarsdottir, Aljona, Saleh, Camilla, Göktürk, Pawel, Baranczewski, Richard, Svensson, Ronnie P-A, Berntsson, Robert, Gustafsson, Kia, Strömberg, Kumar, Sanjiv, Marie-Caroline, Jacques-Cordonnier, Matthieu, Desroses, Anna-Lena, Gustavsson, Roger, Olofsson, Fredrik, Johansson, Evert J, Homan, Olga, Loseva, Lars, Bräutigam, Lars, Johansson, Andreas, Höglund, Anna, Hagenkort, Therese, Pham, Mikael, Altun, Fabienne Z, Gaugaz, Svante, Vikingsson, Bastiaan, Evers, Martin, Henriksson, Karl S A, Vallin, Olov A, Wallner, Lars G J, Hammarström, Elisee, Wiita, Ingrid, Almlöf, Christina, Kalderén, Hanna, Axelsson, Tatjana, Djureinovic, Jordi, Carreras Puigvert, Maria, Häggblad, Fredrik, Jeppsson, Ulf, Martens, Cecilia, Lundin, Bo, Lundgren, Ingrid, Granelli, Annika, Jenmalm Jensen, Per, Artursson, Jonas A, Nilsson, Pål, Stenmark, and Martin, Scobie

Published
2017

2. Correction: Corrigendum: MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Author

Ronnie P.-A. Berntsson, Aljona Saleh, Helge Gad, Martin Henriksson, Ingrid Almlöf, Cecilia E. Ström, Jordi Carreras Puigvert, Pål Stenmark, Fabienne Z. Gaugaz, Cecilia Lundin, Marie-Caroline Jacques-Cordonnier, Ulrika Warpman Berglund Thomas Helleday, Berglind Osk Einarsdottir, Roger Olofsson, Camilla Göktürk, Niklas Schultz, Maria Häggblad, Pawel Baranczewski, Anna-Lena Gustavsson, Olga Loseva, Per Artursson, Karl S. A. Vallin, Hanna Axelsson, Bo Lundgren, Tobias Koolmeister, Kia Strömberg, Christina Kalderén, Ulf Martens, Saeed Eshtad, Jonas Nilsson, Fredrik Johansson, Mikael Altun, Fredrik Jeppsson, Thomas Lundbäck, Evert Homan, Ann-Sofie Jemth, Martin Scobie, Anna Hagenkort, Lars Bräutigam, Annika Jenmalm Jensen, Andreas Höglund, Matthieu Desroses, Linda M. Svensson, Therese M. Pham, Richard Svensson, Kumar Sanjiv, Sylvain A. Jacques, Lars Hammarström, Elisee Wiita, Robert Gustafsson, Tatjana Djureinovic, Olov A. Wallner, Bastiaan Evers, Ingrid Granelli, Svante Vikingsson, and Lars Johansson

Subjects
0301 basic medicine, Genetics, 03 medical and health sciences, Biological data, 030104 developmental biology, Multidisciplinary, Sanitation, DNA replication, medicine, Cancer, Biology, medicine.disease
Abstract

Nature 508, 215–221 (2014); doi:10.1038/nature13181 In this Article, the structure of compound TH650 (4) in Fig. 4a was drawn incorrectly; the correct structure is shown as Fig. 1 to this Corrigendum. Preparative, spectroscopic and biological data associated with this compound are as reported in theArticle, and the error does not influence any of the reported data or interpretations.

Published
2017

3. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Author

Christina Kalderén, Fredrik Jeppsson, Karl S. A. Vallin, Hanna Axelsson, Evert Homan, Thomas Lundbäck, Martin Scobie, Ulrika Warpman Berglund, Per Artursson, Saeed Eshtad, Therese Pham, Lars Bräutigam, Bastiaan Evers, Thomas Helleday, Anna Hagenkort, Bo Lundgren, Richard Svensson, Anna-Lena Gustavsson, Niklas Schultz, Matthieu Desroses, Lars Hammarström, Maria Häggblad, Kumar Sanjiv, Elisee Wiita, Robert Gustafsson, Mikael Altun, Tobias Koolmeister, Aljona Saleh, Pawel Baranczewski, Jonas Nilsson, Sylvain A. Jacques, Andreas Höglund, Cecilia E. Ström, Martin Henriksson, Ingrid Almlöf, Fredrik Johansson, Pål Stenmark, Fabienne Z. Gaugaz, Tatjana Djureinovic, Berglind Osk Einarsdottir, Olov A. Wallner, Annika Jenmalm Jensen, Ronnie P.-A. Berntsson, Helge Gad, Ingrid Granelli, Svante Vikingsson, Linda M. Svensson, Kia Strömberg, Ann-Sofie Jemth, Marie-Caroline Jacques-Cordonnier, Jordi Carreras Puigvert, Roger Olofsson, Camilla Göktürk, Ulf Martens, Lars Johansson, Cecilia Lundin, and Olga Loseva

Subjects
Male, Models, Molecular, DNA damage, Cell Survival, Molecular Conformation, Biology, Redox, Molecular conformation, chemistry.chemical_compound, Mice, Catalytic Domain, Neoplasms, medicine, Animals, Humans, Molecular Targeted Therapy, Enzyme Inhibitors, Pyrophosphatases, Biological sciences, chemistry.chemical_classification, Reactive oxygen species, Multidisciplinary, Cell Death, Nucleotides, DNA replication, Cancer, Deoxyguanine Nucleotides, Reproducibility of Results, medicine.disease, Xenograft Model Antitumor Assays, Phosphoric Monoester Hydrolases, 3. Good health, Cell biology, DNA Repair Enzymes, Pyrimidines, Biochemistry, chemistry, Female, Crystallization, Oxidation-Reduction, DNA, DNA Damage
Abstract

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

Published
2014
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