title: WIKI4, a novel inhibitor of tankyrase and Wnt/ß-catenin signaling.
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.
authors.affiliation: Department of Pharmacology, Seattle, Washington, United States of America ; Institute for Stem Cell and Regenerative Medicine, Seattle, Washington, United States of America.
authors.forename: Richard G
authors.initials: RG
authors.lastname: James
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Davidson
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Bosch
authors.forename: Travis L
authors.initials: TL
authors.lastname: Biechele
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Robin
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Taylor
authors.forename: Michael B
authors.initials: MB
authors.lastname: Major
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Camp
authors.forename: Kerry
authors.initials: K
authors.lastname: Fowler
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Martins
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
mesh_terms: D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D053644:Naphthalimides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*; D054875:Ubiquitination; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D053644:Naphthalimides; D038501:Tankyrases; D014230:Triazoles; D051153:Wnt Proteins; D051176:beta Catenin; C581555:WIKI4 compound; C418109:TNKS protein, human