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

Cancer Res. 2010 Jul 15;70(14):5963-73. doi: 10.1158/0008-5472.CAN-10-1028. Epub 2010 Jul 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor / methods*
  • High-Throughput Screening Assays / methods*
  • Humans
  • L Cells
  • Mice
  • Signal Transduction
  • Transcription, Genetic / drug effects
  • Wnt Proteins / antagonists & inhibitors*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Xenopus laevis
  • Zebrafish


  • Antineoplastic Agents
  • Wnt Proteins