IMU1003, an atrarate derivative, inhibits Wnt/β-catenin signaling

Biochem Biophys Res Commun. 2020 Nov 12;532(3):440-445. doi: 10.1016/j.bbrc.2020.08.031. Epub 2020 Sep 3.

Abstract

Aberrant activation of the canonical Wnt/β-catenin signaling pathway triggers tumorigenesis in various tissues. This study identified an atrarate compound, IMU14, derived from filamentous fungi as an inhibitor of Wnt/β-catenin signaling in phenotypic chemical inhibitor screening of the zebrafish eyeless phenotype. Its derivatization resulted in synthesis of IMU1003 with enhanced Wnt inhibitory activity. IMU1003 inhibited β-catenin/TCF-dependent transcriptional activation and decreased nuclear β-catenin level. In addition, IMU1003 selectively decreased viability and target gene products of the Wnt/β-catenin signaling pathway in human non-colorectal cancer cell lines harboring intact APC and β-catenin. Therefore, atrarate derivatives inhibit Wnt/β-catenin signaling and show anticancer potential, and we developed a new class of chemical backbones for Wnt/β-catenin signaling inhibitors.

Keywords: Atrarate; Inhibitor; Wnt; Zebrafish; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Down-Regulation / drug effects
  • Drug Screening Assays, Antitumor
  • Gene Expression / drug effects
  • HEK293 Cells
  • Humans
  • Hydroxybenzoates / pharmacology*
  • Mutation
  • Wnt Signaling Pathway / drug effects*
  • Wnt Signaling Pathway / genetics
  • Zebrafish / embryology
  • Zebrafish / genetics
  • beta Catenin / metabolism*

Substances

  • Antineoplastic Agents
  • CTNNB1 protein, human
  • Hydroxybenzoates
  • beta Catenin
  • atraric acid