Reference Detail

Ref Type

Journal Article

PMID

(20610623)

Authors

Ewan K, Pajak B, Stubbs M, Todd H, Barbeau O, Quevedo C, Botfield H, Young R, Ruddle R, Samuel L, Battersby A, Raynaud F, Allen N, Wilson S, Latinkic B, Workman P, McDonald E, Blagg J, Aherne W, Dale T

Title

A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	70	14	2010 Jul 15	5963-73	Cancer Res

URL

Abstract Text

The Wnt signaling pathway is frequently deregulated in cancer due to mutations in genes encoding APC, beta-catenin, and axin. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of beta-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This screen illustrates a practical approach to identify small-molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence
CCT031374	CCT031374	1
CCT036477	CCT036477	1
CCT070535	CCT070535	1

Drug Name	Synonyms	Drug Classes	Drug Description
CCT031374		CTNNB1 Inhibitor 27	CCT031374 inhibits TCF/CTNNB1 dependent transcription thereby blocking Wnt signaling, which results in apoptosis (PMID: 20610623, PMID: 26496941).
CCT036477	CCT-036477	CTNNB1 Inhibitor 27	CCT036477 inhibits TCF/CTNNB1 dependent transcription thereby blocking Wnt signaling, which results in apoptosis (PMID: 20610623, PMID: 26522223).
CCT070535		CTNNB1 Inhibitor 27	CCT070535 inhibits TCF/CTNNB1 dependent transcription thereby blocking Wnt signaling, which results in apoptosis (PMID: 20610623).

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	CCT031374	Preclinical	Actionable	In a preclinical study, CCT031374 inhibited Wnt pathway activation and growth of colorectal cancer cell lines harboring APC inactivating mutations in culture (PMID: 20610623).	20610623
APC inact mut	colorectal cancer	sensitive	CCT036477	Preclinical	Actionable	In a preclinical study, CCT036477 inhibited Wnt pathway activation and growth of colorectal cancer cell lines harboring APC inactivating mutations in culture (PMID: 20610623).	20610623
APC inact mut	colorectal cancer	sensitive	CCT070535	Preclinical	Actionable	In a preclinical study, CCT070535 inhibited Wnt pathway activation and growth of colorectal cancer cell lines harboring APC inactivating mutations in culture (PMID: 20610623).	20610623