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Ref Type

Journal Article

PMID

(24819961)

Authors

Delgado ER, Yang J, So J, Leimgruber S, Kahn M, Ishitani T, Shin D, Mustata Wilson G, Monga SP

Title

Identification and characterization of a novel small-molecule inhibitor of β-catenin signaling.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The American journal of pathology	184	7	2014 Jul	2111-22	Am J Pathol

URL

Abstract Text

Hepatocellular carcinoma (HCC), the third most common cause of cancer-related deaths worldwide, lacks effective medical therapy. Large subsets of HCC demonstrate Wnt/β-catenin activation, making this an attractive therapeutic target. We report strategy and characterization of a novel small-molecule inhibitor, ICG-001, known to affect Wnt signaling by disrupting β-catenin-CREB binding protein interactions. We queried the ZINC online database for structural similarity to ICG-001 and identified PMED-1 as the lead compound, with ≥70% similarity to ICG-001. PMED-1 significantly reduced β-catenin activity in hepatoblastoma and several HCC cells, as determined by TOPflash reporter assay, with an IC50 ranging from 4.87 to 32 μmol/L. Although no toxicity was observed in primary human hepatocytes, PMED-1 inhibited Wnt target expression in HCC cells, including those with CTNNB1 mutations, and impaired cell proliferation and viability. PMED-1 treatment decreased β-catenin-CREB binding protein interactions without affecting total β-catenin levels or activity of other common kinases. PMED-1 treatment of Tg(OTM:d2EGFP) zebrafish expressing GFP under the β-catenin/Tcf reporter led to a notable decrease in β-catenin activity. The PMED effect on β-catenin signaling lasted from 12 to 24 hours in vitro and 6 to 15 hours in vivo. Thus, using a rapid and cost-effective computational methodology, we have identified a novel and specific small-molecule inhibitor of Wnt signaling that may have implications for HCC 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
PMED-1	PMED-1	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PMED-1			CTNNB1 Inhibitor 27	PMED-1 inhibits Ctnnb1 and CBP interactions to decrease Wnt signalling thereby inhibiting cell proliferation (PMID: 24819961).

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
CTNNB1 mutant	hepatocellular carcinoma	sensitive	PMED-1	Preclinical	Actionable	In a preclinical study, PMED-1 decreased Wnt expression and decreased proliferation of hepatocellular carcinoma cells with Ctnnb1 mutations (PMID: 24819961).	24819961