論文 - 詳細
| RRC ID | 40024 |
|---|---|
| 著者 | Delgado ER, Yang J, So J, Leimgruber S, Kahn M, Ishitani T, Shin D, Mustata Wilson G, Monga SP. |
| タイトル | Identification and characterization of a novel small-molecule inhibitor of β-catenin signaling. |
| ジャーナル | Am J Pathol |
| Abstract |
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. |
| 巻・号 | 184(7) |
| ページ | 2111-22 |
| 公開日 | 2014-7-1 |
| DOI | 10.1016/j.ajpath.2014.04.002 |
| PII | S0002-9440(14)00219-3 |
| PMID | 24819961 |
| PMC | PMC4076560 |
| MeSH | Animals Bridged Bicyclo Compounds, Heterocyclic / pharmacology CREB-Binding Protein / metabolism Carcinoma, Hepatocellular / metabolism Cell Line, Tumor Drug Discovery Humans Inhibitory Concentration 50 Liver Neoplasms / metabolism Pyrimidinones / pharmacology Structure-Activity Relationship Wnt Signaling Pathway / drug effects* Zebrafish beta Catenin / antagonists & inhibitors* beta Catenin / metabolism |
| IF | 3.491 |
| 引用数 | 16 |
| WOS 分野 | PATHOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ゼブラフィッシュ | Tg(6xTcf/LefBS-miniP:d2EGFP) |