WIKI4, a novel inhibitor of tankyrase and Wnt/ß-catenin signaling

PLoS One. 2012;7(12):e50457. doi: 10.1371/journal.pone.0050457. Epub 2012 Dec 5.


The Wnt/ß-catenin signaling pathway controls important cellular events during development and often contributes to disease when dysregulated. Using high throughput screening we have identified a new small molecule inhibitor of Wnt/ß-catenin signaling, WIKI4. WIKI4 inhibits expression of ß-catenin target genes and cellular responses to Wnt/ß-catenin signaling in cancer cell lines as well as in human embryonic stem cells. Furthermore, we demonstrate that WIKI4 mediates its effects on Wnt/ß-catenin signaling by inhibiting the enzymatic activity of TNKS2, a regulator of AXIN ubiquitylation and degradation. While TNKS has previously been shown to be the target of small molecule inhibitors of Wnt/ß-catenin signaling, WIKI4 is structurally distinct from previously identified TNKS inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Naphthalimides / pharmacology*
  • Signal Transduction / drug effects*
  • Tankyrases / antagonists & inhibitors*
  • Triazoles / pharmacology*
  • Ubiquitination
  • Wnt Proteins / antagonists & inhibitors*
  • Wnt Proteins / metabolism
  • beta Catenin / antagonists & inhibitors*
  • beta Catenin / metabolism


  • Enzyme Inhibitors
  • Naphthalimides
  • Triazoles
  • WIKI4 compound
  • Wnt Proteins
  • beta Catenin
  • Tankyrases
  • TNKS protein, human