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An Antagonist of Dishevelled Protein-Protein Interaction Suppresses ß-Catenin–Dependent Tumor Cell Growth

Departments of ¹ Pharmaceutical Chemistry and ² Cellular and Molecular Pharmacology; ³ Thoracic Oncology Laboratory, Department of Surgery; and ⁴ Genome Analysis Core, Cancer Center, University of California San Francisco, San Francisco, California; ⁵ Department of Structural Biology and ⁶ Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital; ⁷ Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee; and ⁸ Division of Medical Oncology, Tokai University School of Medicine, Isehara, Japan

Requests for reprints: Naoaki Fujii, Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, M/S1000, 332 North Lauderdale Street, Memphis, TN 38105. Phone: 901-495-5854; Fax: 901-495-5715; E-mail: Naoaki.Fujii{at}stjude.org.

Recent progress in the development of inhibitors of protein-protein interactions has opened the door for developing drugs that act by novel and selective mechanisms. Building on that work, we designed a small-molecule inhibitor of the Wnt signaling pathway, which is aberrantly activated across a wide range of human tumors. The compound, named FJ9, disrupts the interaction between the Frizzed-7 Wnt receptor and the PDZ domain of Dishevelled, down-regulating canonical Wnt signaling and suppressing tumor cell growth. The antitumorigenic effects of FJ9 were pronounced, including induction of apoptosis in human cancer cell lines and tumor growth inhibition in a mouse xenograft model. FJ9 is thus among the first non-peptide inhibitors to show therapeutic efficacy through disruption of PDZ protein-protein interactions. [Cancer Res 2007;67(2):573–9]

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				Correction: Antagonist of Dishevelled Suppressing Tumor Cell Growth Cancer Res., March 1, 2007; 67(5): 2389 - 2389. [Full Text] [PDF]