A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription

Research output: Contribution to journalArticle

Authors

  • Kenneth Ewan
  • Bozena Pajak
  • Mark Stubbs
  • Helen Todd
  • Olivier Barbeau
  • Camilo Quevedo
  • Rodrigo Young
  • Ruth Ruddle
  • Lee Samuel
  • Alysia Battersby
  • Florence Raynaud
  • Nicholas Allen
  • Stephen Wilson
  • Branko Latinkic
  • Paul Workman
  • Edward McDonald
  • Julian Blagg
  • Wynne Aherne
  • Trevor Dale

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.

Details

Original languageEnglish
Pages (from-to)5963-73
Number of pages11
JournalCancer Research
Volume70
Issue number14
Publication statusPublished - 15 Jul 2010

Keywords

  • Animals, Antineoplastic Agents, Cell Line, Tumor, Drug Screening Assays, Antitumor, High-Throughput Screening Assays, Humans, L Cells (Cell Line), Mice, Signal Transduction, Transcription, Genetic, Wnt Proteins, Xenopus laevis, Zebrafish