1. WIKI4, a Novel Inhibitor of Tankyrase and Wnt/beta-Catenin Signaling
- Author
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Morrisey, E, James, RG, Davidson, KC, Bosch, KA, Biechele, TL, Robin, NC, Taylor, RJ, Major, MB, Camp, ND, Fowler, K, Martins, TJ, Moon, RT, Morrisey, E, James, RG, Davidson, KC, Bosch, KA, Biechele, TL, Robin, NC, Taylor, RJ, Major, MB, Camp, ND, Fowler, K, Martins, TJ, and Moon, RT
- Abstract
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.
- Published
- 2012