An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth.

Abstract	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.
Authors	Naoaki Fujii, Liang You, Zhidong Xu, Kazutsugu Uematsu, Jufang Shan, Biao He, Iwao Mikami, Lillian R Edmondson, Geoffrey Neale, Jie Zheng, R Kiplin Guy, David M Jablons
Journal	Cancer research (Cancer Res) Vol. 67 Issue 2 Pg. 573-9 (Jan 15 2007) ISSN: 0008-5472 [Print] United States
PMID	17234765 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing Dishevelled Proteins FJ9 compound FZD7 protein, human Frizzled Receptors Indoles Phosphoproteins Receptors, G-Protein-Coupled Wnt Proteins beta Catenin
Topics	Adaptor Proteins, Signal Transducing (antagonists & inhibitors, metabolism) Animals Apoptosis (drug effects) Cell Growth Processes (drug effects, physiology) Cell Line, Tumor Dishevelled Proteins Female Frizzled Receptors (antagonists & inhibitors, metabolism) HCT116 Cells HeLa Cells Humans Indoles (pharmacology) Mice Mice, Nude Models, Molecular Phosphoproteins (antagonists & inhibitors, metabolism) Protein Structure, Tertiary Receptors, G-Protein-Coupled (antagonists & inhibitors, metabolism) Signal Transduction (drug effects) Wnt Proteins (antagonists & inhibitors, metabolism) Xenograft Model Antitumor Assays beta Catenin (antagonists & inhibitors, physiology)

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