Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4

PLoS One. 2013 Jun 6;8(6):e65404. doi: 10.1371/journal.pone.0065404. Print 2013.

Abstract

Recently a novel inhibitor of Wnt signaling was discovered. The compound, WIKI4, was found to act through tankyrase inhibition and regulate β-catenin levels in many cancer cell lines and human embryonic stem cells. Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested. The binding mode of the compound to tankyrase 2 was determined by protein X-ray crystallography to 2.4 Å resolution. The structure revealed a novel binding mode to the adenosine subsite of the donor NAD(+) binding groove of the catalytic domain. Our results form a structural basis for further development of potent and selective tankyrase inhibitors based on the WIKI4 scaffold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / chemistry*
  • Catalytic Domain
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Enzyme Inhibitors
  • Humans
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • NAD / chemistry
  • Naphthalimides / chemistry*
  • Protein Binding
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Sensitivity and Specificity
  • Tankyrases / antagonists & inhibitors
  • Tankyrases / chemistry*
  • Tankyrases / genetics
  • Triazoles / chemistry*
  • Wnt Signaling Pathway

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Naphthalimides
  • Recombinant Proteins
  • Triazoles
  • WIKI4 compound
  • NAD
  • TNKS2 protein, human
  • Tankyrases

Grants and funding

The work was funded by Biocenter Oulu (http://www.oulu.fi/biocenter/) and by Sigrid Jusélius foundation (http://www.sigridjuselius.fi/). MN and HV are members of the National Doctoral Programme of Informational and Structural Biology. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under BioStruct-X (grant agreement N°283570). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.