ZFIN ID: ZDB-PUB-140514-7
Identification and Characterization of a Novel Small-Molecule Inhibitor of beta-Catenin Signaling
Delgado, E.R., Yang, J., So, J., Leimgruber, S., Kahn, M., Ishitani, T., Shin, D., Wilson, G.M., Monga, S.P.
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.
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┬ávitro and 6 to 15 hours in┬ávivo. 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.