• A Corrigendum to this article was published on 26 April 2017

This article has been updated

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.

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  • 10 April 2014

    Asterisks were missing in Fig. 5c and have now been added.

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Acknowledgements

We thank scientists at BESSY, ESRF, Max-Lab and the Swiss Light Source for structural biology data collection support, PSF for protein purification, GE Healthcare for instrument access, HTSRC (Rockefeller University) for iTC200 calorimeter access, S. Nordstrand for animal support, and L. Ny, U. Stierner and J. Mattsson for discussions. The Helleday Laboratory is primarily funded by the Torsten and Ragnar Söderberg Foundation (T.H.). This project is primarily supported by The Knut and Alice Wallenberg Foundation. Further support was received from the Swedish Research Council (T.H., A.J.J., P.A., P.S., J.A.N.), the European Research Council (T.H.), Swedish Cancer Society (T.H., J.A.N.), the Swedish Children’s Cancer Foundation (T.H.), AFA insurance (T.H.), the Swedish Pain Relief Foundation (T.H.), The Cancer Society in Stockholm (T.H.), the Wenner-Gren Foundations (P.S.), the Swedish Foundation for Strategic Research (P.S.), the Dutch Cancer Society (B.E.), EMBO LTF (R.B.), Region Västra Götaland (J.A.N.), BioCARE (J.A.N.), the Swiss National Science Foundation (F.Z.G.) and the Nicholson Exchange Program (T.L.). Chemical Biology Consortium Sweden (CBCS) is primarily funded by the Swedish Research Council. CBCS acknowledge Swedish Orphan Biovitrum for their donation of a small-molecule infrastructure including a compound collection.

Author information

Author notes

    • Helge Gad
    • , Tobias Koolmeister
    • , Ann-Sofie Jemth
    • , Saeed Eshtad
    • , Sylvain A. Jacques
    •  & Cecilia E. Ström

    These authors contributed equally to this work.

    • Bastiaan Evers
    •  & Tatjana Djureinovic

    Present addresses: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.).

Affiliations

  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

    • Helge Gad
    • , Tobias Koolmeister
    • , Ann-Sofie Jemth
    • , Saeed Eshtad
    • , Sylvain A. Jacques
    • , Cecilia E. Ström
    • , Niklas Schultz
    • , Thomas Lundbäck
    • , Camilla Göktürk
    • , Pawel Baranczewski
    • , Kia Strömberg
    • , Kumar Sanjiv
    • , Marie-Caroline Jacques-Cordonnier
    • , Matthieu Desroses
    • , Anna-Lena Gustavsson
    • , 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
    • , Jordi Carreras Puigvert
    • , Fredrik Jeppsson
    • , Cecilia Lundin
    • , Annika Jenmalm Jensen
    • , Martin Scobie
    • , Ulrika Warpman Berglund
    •  & Thomas Helleday
  2. Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden

    • Linda M. Svensson
    • , Ronnie P.-A. Berntsson
    • , Robert Gustafsson
    •  & Pål Stenmark
  3. Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden

    • Thomas Lundbäck
    • , Richard Svensson
    • , Anna-Lena Gustavsson
    • , Lars Johansson
    • , Lars G. J. Hammarström
    • , Hanna Axelsson
    • , Annika Jenmalm Jensen
    •  & Per Artursson
  4. Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, Department of Surgery, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden

    • Berglind Osk Einarsdottir
    • , Roger Olofsson
    •  & Jonas A. Nilsson
  5. Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden

    • Aljona Saleh
    •  & Ingrid Granelli
  6. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden

    • Pawel Baranczewski
    • , Richard Svensson
    • , Fabienne Z. Gaugaz
    •  & Per Artursson
  7. Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden

    • Fredrik Johansson
    •  & Tatjana Djureinovic
  8. Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, S-58185 Linköping, Sweden

    • Svante Vikingsson
  9. Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden

    • Maria Häggblad
    • , Ulf Martens
    •  & Bo Lundgren

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Contributions

T.H. devised concept and supervised the project. H.G., S.E., N.S., C.E.S., L.B., K.Sa., F.Jo., A.Hö., B.E., T.D., M.A., A.Ha., C.L., U.W.B. and T.H. designed, performed and analysed cell biology experiments. A-S.J., T.L., F.Je., O.L., K.St., T.K., M.Hä., U.M., B.L., L.J, A.J.J., E.W., C.K., I.A., S.A.J., U.W.B. and T.H. designed, performed and analysed biochemical and high-throughput experiments. L.M.S., R.P.-A.B., R.G. and P.S. designed, performed and analysed structural biology experiments. T.K., S.A.J., M.D., M.-C.J.-C., L.J., L.G.J.H., M.He, K.S.A.V., O.A.W., A.J.J., M.S. and T.H. designed, performed and analysed medicinal chemistry experiments. A.-L.G., J.C.P., E.J.H. and M.D. performed computational chemistry analysis and/or support. C.G., B.O.E., A.S., K.Sa., P.B., R.S., F.Z.G., I.G., P.A., T.P., S.V., J.A.N. and U.W.B. designed, performed and analysed ADME, pharmacology and in vivo experiments. R.O. performed surgery, and clinical follow-up, H.G., U.W.B. and T.H. wrote the paper. All authors discussed results and approved the manuscript.

Competing interests

A patent has been filed with data generated in this manuscript where T.H., M.S., T.K., S.A.J., M.D., M-C.JC. are listed as inventors.

Corresponding author

Correspondence to Thomas Helleday.

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    Supplementary Methods

    This file contains details of the synthesis of specific MTH1 inhibitors.

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https://doi.org/10.1038/nature13181

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