SRI36160 is a specific inhibitor of Wnt/β-catenin signaling in human pancreatic and colorectal cancer cells

Cancer Lett. 2017 Mar 28;389:41-48. doi: 10.1016/j.canlet.2016.12.030. Epub 2016 Dec 30.

Abstract

Activation of Wnt/β-catenin signaling is associated with pancreatic and colorectal cancer, among others. To-date, there are no FDA-approved small molecule Wnt/β-catenin inhibitors and many past efforts resulted in compounds with undesirable off-target effects. We recently identified a series of benzimidazole analogs as potent inhibitors of Wnt/β-catenin signaling. Here, we show that the lead compound SRI36160 displayed selective Wnt inhibition and potent antiproliferative activity in pancreatic and colorectal cancer cells. Moreover, SRI36160 had no effect on STAT3 and mTORC1 signaling in pancreatic and colorectal cancer cells, and was not effective in inhibiting proliferation of non-cancerous cells. Our findings suggest that this series of benzimidazole analogs presents a novel approach for the treatment of Wnt-dependent cancers such as colorectal and pancreatic cancer.

Keywords: Benzimidazole; Drug discovery; Niclosamide; Targeted therapy; Wnt signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Retracted Publication

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Animals
  • Benzimidazoles / pharmacology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / physiology
  • Mice
  • Mutation
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Phosphorylation
  • Wnt Proteins / antagonists & inhibitors*
  • Wnt Signaling Pathway / drug effects*
  • Wnt3A Protein / physiology
  • beta Catenin / antagonists & inhibitors*
  • beta Catenin / genetics

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • Benzimidazoles
  • CTNNB1 protein, human
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • SRI36160
  • WNT3A protein, human
  • Wnt Proteins
  • Wnt3A Protein
  • beta Catenin