Tankyrases as drug targets

Authors

  • Lari Lehtiö,

    Corresponding author
    1. Biocenter Oulu and Department of Biochemistry, University of Oulu, Finland
    • Correspondence

      L. Lehtiö, Biocenter Oulu and Department of Biochemistry, P.O. Box 3000, 90014 University of Oulu, Oulu, Finland

      Fax: +358 2 9448 1141

      Tel: +358 2 9448 1169

      E-mail: lari.lehtio@oulu.fi

      S. Krauss, SFI-CAST Biomedical Innovation Center, Unit for Cell Signaling, Oslo University Hospital, Forskningsparken, Gaustadalleen 21, 0349, Oslo, Norway

      Tel: +47 22958152

      E-mail: stefan.krauss@rr-research.no

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  • Nai-Wen Chi,

    1. Veterans Affairs San Diego Healthcare System, University of California, San Diego, CA, USA
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  • Stefan Krauss

    Corresponding author
    1. Oslo University Hospital, SFI-CAST Biomedical Innovation Center, Unit for Cell Signaling, Forskningsparken, Gaustadalleen, Norway
    • Correspondence

      L. Lehtiö, Biocenter Oulu and Department of Biochemistry, P.O. Box 3000, 90014 University of Oulu, Oulu, Finland

      Fax: +358 2 9448 1141

      Tel: +358 2 9448 1169

      E-mail: lari.lehtio@oulu.fi

      S. Krauss, SFI-CAST Biomedical Innovation Center, Unit for Cell Signaling, Oslo University Hospital, Forskningsparken, Gaustadalleen 21, 0349, Oslo, Norway

      Tel: +47 22958152

      E-mail: stefan.krauss@rr-research.no

    Search for more papers by this author

Abstract

Tankyrase 1 and tankyrase 2 are poly(ADP-ribosyl)ases that are distinguishable from other members of the enzyme family by the structural features of the catalytic domain, and the presence of a sterile α-motif multimerization domain and an ankyrin repeat protein-interaction domain. Tankyrases are implicated in a multitude of cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt–β-catenin signaling, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly(ADP-ribosyl)ation, and regulate protein interactions and stability. The proposed roles of tankyrases in disease-relevant cellular processes have made them attractive drug targets. Recently, several inhibitors have been identified. The selectivity and potency of these small molecules can be rationalized by how they fit within the NAD+-binding groove of the catalytic domain. Some molecules bind to the nicotinamide subsite, such as generic diphtheria toxin-like ADP-ribosyltransferase inhibitors, whereas others bind to a distinct adenosine subsite that diverges from other diphtheria toxin-like ADP-ribosyltransferases and confers specificity. A highly potent dual-site inhibitor is also available. Within the last few years, tankyrase inhibitors have proved to be useful chemical probes and potential lead compounds, especially for specific cancers.

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