title: A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription.
abstract: The Wnt signaling pathway is frequently deregulated in cancer due to mutations in genes encoding APC, beta-catenin, and axin. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of beta-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This screen illustrates a practical approach to identify small-molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors.
authors.affiliation: School of Bioscience, Cardiff University, Cardiff, United Kingdom.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ewan
authors.forename: Bozena
authors.initials: B
authors.lastname: Pajak
authors.forename: Mark
authors.initials: M
authors.lastname: Stubbs
authors.forename: Helen
authors.initials: H
authors.lastname: Todd
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbeau
authors.forename: Camilo
authors.initials: C
authors.lastname: Quevedo
authors.forename: Hannah
authors.initials: H
authors.lastname: Botfield
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Young
authors.forename: Ruth
authors.initials: R
authors.lastname: Ruddle
authors.forename: Lee
authors.initials: L
authors.lastname: Samuel
authors.forename: Alysia
authors.initials: A
authors.lastname: Battersby
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Nicholas
authors.initials: N
authors.lastname: Allen
authors.forename: Stephen
authors.initials: S
authors.lastname: Wilson
authors.forename: Branko
authors.initials: B
authors.lastname: Latinkic
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Edward
authors.initials: E
authors.lastname: McDonald
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
authors.forename: Wynne
authors.initials: W
authors.lastname: Aherne
authors.forename: Trevor
authors.initials: T
authors.lastname: Dale
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007739:L Cells; D051379:Mice; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D051153:Wnt Proteins