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

Evan R. Delgado, Jing Yang, Juhoon So, Stephanie Leimgruber, Michael Kahn, Tohru Ishitani, Donghun Shin, Gabriela Mustata Wilson, Satdarshan P. Monga

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16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2111-2122
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number7
DOIs
Publication statusPublished - Jan 1 2014

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Delgado, E. R., Yang, J., So, J., Leimgruber, S., Kahn, M., Ishitani, T., Shin, D., Mustata Wilson, G., & Monga, S. P. (2014). Identification and characterization of a novel small-molecule inhibitor of β-catenin signaling. American Journal of Pathology, 184(7), 2111-2122. https://doi.org/10.1016/j.ajpath.2014.04.002