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
Nat Chem Biol. 2010 6 (11): 829-36

PMID: 20890287 · PMCID: PMC3681608 · DOI:10.1038/nchembio.453

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.

MeSH Terms (23)

Adaptor Proteins, Signal Transducing Adenomatous Polyposis Coli Animals Axin Protein beta Catenin Casein Kinase I Casein Kinase Ialpha Cell Extracts Cell Line, Tumor Cell Proliferation Colonic Neoplasms Dose-Response Relationship, Drug Enzyme Activation Enzyme Inhibitors Humans Intracellular Signaling Peptides and Proteins Oocytes Pyrvinium Compounds Repressor Proteins Signal Transduction Wnt Proteins Xenopus laevis Xenopus Proteins

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