RRC ID 40024
Author 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.
Journal 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.
Volume 184(7)
Pages 2111-22
Published 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
Times Cited 16
Zebrafish Tg(6xTcf/LefBS-miniP:d2EGFP)