Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 23762361.
- Also identified by DOI 10.1371/journal.pone.0065404 and PMC identifier 3675114.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Antineoplastic Agents
- Naphthalimides
- Tankyrases
- Triazoles