Identification and characterization of a novel small-molecule inhibitor of β-catenin signaling

Am J Pathol. 2014 Jul;184(7):2111-22. doi: 10.1016/j.ajpath.2014.04.002.

Evan R Delgado ¹, Jing Yang ¹, Juhoon So ², Stephanie Leimgruber ³, Michael Kahn ⁴, Tohru Ishitani ⁵, Donghun Shin ², Gabriela Mustata Wilson ⁶, Satdarshan P Monga ⁷

Affiliations

1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
2 Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
3 Department of Pharmacology, University of Virginia, Charlottesville, Virginia, Los Angeles, California.
4 Department of Molecular Pharmacology and Toxicology, School of Pharmacy, Keck School of Medicine, University of Southern California, Los Angeles, California.
5 Division of Cell Regulation Systems, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
6 Department of Health Services and Health Administration, University of Southern Indiana, Evansville, Indiana. Electronic address: gmwilson@usi.edu.
7 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: smonga@pitt.edu.

PMID: 24819961 DOI: 10.1016/j.ajpath.2014.04.002

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-164520

PMED-1

β-catenin Inhibitor

Wnt

Cancer

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