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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. | ||||||||||||
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| 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 |