2. Academic Validation
  3. A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription

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.
Kenneth Ewan 1,  Bozena Pajak,  Mark Stubbs,  Helen Todd,  Olivier Barbeau,  Camilo Quevedo,  Hannah Botfield,  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
Affiliations

Affiliation

  • 1 School of Bioscience, Cardiff University, Cardiff, United Kingdom.
PMID: 20610623 DOI: 10.1158/0008-5472.CAN-10-1028
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.

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