PUBLICATION
Identification and Characterization of a Novel Small-Molecule Inhibitor of beta-Catenin Signaling
- Authors
- Delgado, E.R., Yang, J., So, J., Leimgruber, S., Kahn, M., Ishitani, T., Shin, D., Wilson, G.M., Monga, S.P.
- ID
- ZDB-PUB-140514-7
- Date
- 2014
- Source
- The American journal of pathology 184(7): 2111-22 (Journal)
- Registered Authors
- Ishitani, Tohru, Shin, Donghun, So, Juhoon
- Keywords
- none
- MeSH Terms
-
- 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
- PubMed
- 24819961 Full text @ Am. J. Pathol.
Citation
Delgado, E.R., Yang, J., So, J., Leimgruber, S., Kahn, M., Ishitani, T., Shin, D., Wilson, G.M., Monga, S.P. (2014) Identification and Characterization of a Novel Small-Molecule Inhibitor of beta-Catenin Signaling. The American journal of pathology. 184(7):2111-22.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping