• 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, Martin Scobie, Ulrika Warpman Berglund, and Thomas Helleday.
• 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2].
• Nature. 2014 Apr 10;508(7495):215-21.

AbstractCancers 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.

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