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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|