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Ref Type Journal Article
PMID (20890287)
Authors 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
Title Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
Journal Vol Issue Date Pages Journal Short Title
Nature chemical biology 6 11 2010 Nov 829-36 Nat Chem Biol
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Pyrvinium Pyrvinium 1 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
Pyrvinium Pyrvinium Pamoate CTNNB1 Inhibitor 27 STAT3 Inhibitor 26 Pyrvinium blocks STAT3 and activates CK1-alpha, which leads to CTNNB1 degradation and inhibition of Wnt signaling thereby inducing apoptosis (PMID: 20890287, PMID: 32298693).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC inact mut colorectal cancer sensitive Pyrvinium Preclinical Actionable In a preclinical study, Pyrvinium inhibited Wnt signaling and decreased viability of colon cancer cells harboring APC mutations in culture (PMID: 20890287). 20890287