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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