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|Ref Type||Journal Article|
|Authors||Waaler J, Machon O, von Kries JP, Wilson SR, Lundenes E, Wedlich D, Gradl D, Paulsen JE, Machonova O, Dembinski JL, Dinh H, Krauss S|
|Title||Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth.|
|Date||2011 Jan 01|
|Abstract Text||Canonical Wnt signaling is deregulated in several types of human cancer where it plays a central role in tumor cell growth and progression. Here we report the identification of 2 new small molecules that specifically inhibit canonical Wnt pathway at the level of the destruction complex. Specificity was verified in various cellular reporter systems, a Xenopus double-axis formation assay and a gene expression profile analysis. In human colorectal cancer (CRC) cells, the new compounds JW67 and JW74 rapidly reduced active β-catenin with a subsequent downregulation of Wnt target genes, including AXIN2, SP5, and NKD1. Notably, AXIN2 protein levels were strongly increased after compound exposure. Long-term treatment with JW74 inhibited the growth of tumor cells in both a mouse xenograft model of CRC and in Apc(Min) mice (multiple intestinal neoplasia, Min). Our findings rationalize further preclinical and clinical evaluation of these new compounds as novel modalities for cancer treatment.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|JW67||JW 67||CTNNB1 Inhibitor 26||JW67 is a small molecule that inhibits canonical Wnt signaling, potentially resulting in decreased tumor cell growth (PMID: 21199802).|
|JW74||JW 74||CTNNB1 Inhibitor 26||JW74 is a small molecule that inhibits canonical Wnt signaling, potentially resulting in decreased tumor cell growth (PMID: 21199802, PMID: 30142387).|
|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 mutant||colorectal cancer||sensitive||JW74||Preclinical||Actionable||In a preclinical study, JW74 reduced tumor formation and growth in a mouse model of colorectal cancer harboring an APC mutation (PMID: 21199802).||21199802|
|APC Q1338*||colorectal cancer||sensitive||JW67||Preclinical||Actionable||In a preclinical study, JW67 inhibited Wnt signaling and decreased proliferation of colorectal cancer cells harboring APC Q1338* in culture (PMID: 21199802).||21199802|
|APC Q1338*||colorectal cancer||sensitive||JW74||Preclinical||Actionable||In a preclinical study, JW74 inhibited Wnt signaling and decreased growth of colorectal cancer cells harboring APC Q1338* in culture and in xenograft models (PMID: 21199802).||21199802|