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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: [+]

Species referenced: Xenopus
Genes referenced: csnk1a1 ctnnb1 krt8.1 pygo2
GO keywords: axis specification [+]

Disease Ontology terms: familial adenomatous polyposis
References [+] :
Aoki, Nuclear endpoint of Wnt signaling: neoplastic transformation induced by transactivating lymphoid-enhancing factor 1. 1999, Pubmed