Reference Detail

Ref Type

Journal Article

PMID

(21199802)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	71	1	2011 Jan 01	197-205	Cancer Res

URL

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.

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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
JW67	JW67	1	0
JW74	JW74	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
JW67		JW 67	CTNNB1 Inhibitor 27	JW67 is a small molecule that inhibits canonical Wnt signaling, potentially resulting in decreased tumor cell growth (PMID: 21199802).
JW74		JW 74	CTNNB1 Inhibitor 27	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 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
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