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Research Articles: Therapeutics, Targets, and Development

Evaluation of a chemical library of small-molecule Dishevelled antagonists that suppress tumor growth by down-regulating T-cell factor–mediated transcription

¹ Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California; and ² Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee

Requests for reprints: Naoaki Fujii, Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105. Phone: 901-495-5854; Fax: 901-495-5715. E-mail: naoaki.fujii{at}stjude.org

Abstract

We describe the rational generation of small-molecule agents that suppress tumor cell growth by down-regulating canonical Wnt signaling. We first produced a chemical library of the derivatives of indole-2-ketones and carbinols; we then screened them by using scalable assays of biochemical antagonism of Dishevelled-1 PDZ domain interactions and cell-based assays of Dishevelled-1–driven T-cell factor–mediated transcription. Compounds showing parallel effects in these assays were tested for selective induction of apoptosis in cancer cells. A new compound (24) that met the criteria for high biochemical antagonism, T-cell factor–mediated transcription, and induction of tumor-selective apoptosis was found to significantly suppress the growth of tumor xenografts in mice. [Mol Cancer Ther 2008;7(6):1633–8]

Grant support: American Lebanese Syrian Associated Charities (C. Punchihewa and N. Fujii) and NIH grant R01 CA 093708-01A3, Larry Hall and Zygielbaum Memorial Trust, and Kazan, McClain, Edises, Abrams, Fernandez, Lyons & Farrise Foundation (L. You, Z. Xu, and D.M. Jablons).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁴ Uemotsu K and You L, unpublished data.

Received 2/12/08; accepted 3/12/08.