Useful Damage

Useful Damage

Author: Melania Tesio

The nucleotide pool sanitization enzyme (MTH1) removes oxidized nucleotides from the cellular pool of nucleoside triphosphates. By doing so, MTH1 prevents the incorporation of oxidized DNA bases into nucleic acids, ultimately counteracting DNA damage. Two independent studies demonstrated that small MTH1 inhibitors halt cancer growth.

Tomas Helleday, Karolinska Institute, Stockholm, Sweden, and colleagues have developed a small molecule (TH588, pictured) and demonstrated that it selectively blocks MTH1, thereby promoting the incorporation of oxidized nucleotides into DNA. Consequently, TH588 caused DNA damage and prevented cancer growth.
Similarly, Giulio Superti-Furga, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria, and coworkers have demonstrated that the (S)-enantiomer of the kinase inhibitor crizotinib potently inhibits MTH1, thereby suppressing tumor growth.

  • MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool,
    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, Thomas Helleday,
    Nature 2014, 508, 215–221.
    DOI: 10.1038/nature13181
  • Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy,
    Kilian V. M. Huber, Eidarus Salah, Branka Radic, Manuela Gridling, Jonathan M. Elkins, Alexey Stukalov, Ann-Sofie Jemth, Camilla Göktürk, Kumar Sanjiv, Kia Strömberg, Therese Pham, Ulrika Warpman Berglund, Jacques Colinge, Keiryn L. Bennett, Joanna I. Loizou, Thomas Helleday, Stefan Knapp, Giulio Superti-Furga,
    Nature 2014, 508, 222–227.
    DOI: 10.1038/nature13194

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