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Nat Chem Biol. November 1, 2010; 6 (11): 829-36.

Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.

Thorne CA , Hanson AJ , Schneider J , Tahinci E , Orton D , Cselenyi CS , Jernigan KK , Meyers KC , Hang BI , Waterson AG , Kim K , Melancon B , Ghidu VP , Sulikowski GA , LaFleur B , Salic A , Lee LA , Miller DM , Lee E .

Wnt/β-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote β-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC(50) of ∼10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.

PubMed ID: 20890287
PMC ID: PMC3681608
Article link: Nat Chem Biol.
Grant support: 1 R01 GM081635-01 NIGMS NIH HHS , 1 R01 NS26115 NINDS NIH HHS , 5 T 32 DK007563 NIDDK NIH HHS , 5 T32 GM007347 NIGMS NIH HHS , 5 T32 HD007502 NICHD NIH HHS , 5U01 CA084239 NCI NIH HHS , P50 CA95103 NCI NIH HHS , T32 CA09592 NCI NIH HHS , R01 GM081635-05 NIGMS NIH HHS , P30 CA068485 NCI NIH HHS , P30 DK058404 NIDDK NIH HHS , P30 ES000267 NIEHS NIH HHS , P50 GM015431 NIGMS NIH HHS , R01 GM058008 NIGMS NIH HHS , R01 GM081635 NIGMS NIH HHS , R33 CA086243 NCI NIH HHS , U01 CA084239 NCI NIH HHS , R01 GM074044 NIGMS NIH HHS , T32 HD007502 NICHD NIH HHS

Genes referenced: csnk1a1 pygo2

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