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

• Published in: PloS one Vol. 8; no. 6; p. e65404
• Main Authors: Haikarainen, Teemu, Venkannagari, Harikanth, Narwal, Mohit, Obaji, Ezeogo, Lee, Hao-Wei, Nkizinkiko, Yves, Lehtiö, Lari
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06-06-2013; Public Library of Science (PLoS)
• Subjects: Adenosine; Amino Acid Sequence; Antineoplastic Agents - chemistry; Binding; Biochemistry; Biology; Cancer; Catalysis; Catalytic Domain; Cell Line, Tumor; Cloning; Crystal structure; Crystallography; Crystallography, X-Ray; DNA damage; Embryo cells; Embryonic stem cells; Enzyme Inhibitors; Enzymes; Humans; Inhibition; Inhibitors; Kinases; Materials Science; Medicine; Molecular Docking Simulation; Molecular Sequence Data; NAD; NAD - chemistry; Naphthalimides - chemistry; Pharmaceutical sciences; Protein Binding; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Selectivity; Senescence; Sensitivity and Specificity; Signaling; Stem cells; Tankyrases - antagonists & inhibitors; Tankyrases - chemistry; Tankyrases - genetics; Telomerase; Triazoles - chemistry; Tumor cell lines; Wnt protein; Wnt Signaling Pathway; X-ray crystallography; β-Catenin; Finland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0065404

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.