Aberrant activation of the Wnt signaling pathway has been implicated in the development of tumors. However, because the Wnt family has multiple functions, inhibition of all Wnt signaling is not an optimal strategy for tumor therapy. One solution is to target only Wnt signaling molecules that contribute to tumorigenesis. Wnt signaling via the Frizzled-7 (Frz7) receptor is reported to have oncogenic potential. The authors have previously shown that Frz7 interacts directly with a PDZ protein interaction domain of Dishevelled (DVL), a Wnt signaling molecule, and that elimination of this domain reduces Tcf-mediated transcription and suppresses tumorigenesis of mesothelioma cells. Therefore, disruption of the Frz7-DVL PDZ protein-protein interaction offers a strategy to selectively target oncogenic Wnt signaling. To test this hypothesis, the authors designed a new small molecule inhibitor, FJ9 (upper right). Chemical shift experiments showed that FJ9 binds to the DVL PDZ domain in a manner similar to Frz7 binding (main panel), thereby antagonizing Frz7-DVL interaction and down-regulating canonical Wnt signaling. The pronounced tumor-suppressive effects of FJ9 included selective induction of apoptosis in cancer cell lines and inhibition of tumor growth in a mouse xenograft model. FJ9 is thus among the first nonpeptide inhibitors to show therapeutic anticancer efficacy through disruption of PDZ protein-protein interactions. For details, see the article by Fujii et al. on page 573 of this issue.

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