A zebrafish chemical suppressor screening identifies small molecule inhibitors of the Wnt/β-catenin pathway

Chem Biol. 2014 Apr 24;21(4):530-540. doi: 10.1016/j.chembiol.2014.02.015. Epub 2014 Mar 27.

Abstract

Genetic screening for suppressor mutants has been successfully used to identify important signaling regulators. Using an analogy to genetic suppressor screening, we developed a chemical suppressor screening method to identify inhibitors of the Wnt/β-catenin signaling pathway. We used zebrafish embryos in which chemically induced β-catenin accumulation led to an "eyeless" phenotype and conducted a pilot screening for compounds that restored eye development. This approach allowed us to identify geranylgeranyltransferase inhibitor 286 (GGTI-286), a geranylgeranyltransferase (GGTase) inhibitor. Our follow-up studies showed that GGTI-286 reduces nuclear localization of β-catenin and transcription dependent on β-catenin/T cell factor in mammalian cells. In addition to pharmacological inhibition, GGTase gene knockdown also attenuates the nuclear function of β-catenin. Overall, we validate our chemical suppressor screening as a method for identifying Wnt/β-catenin pathway inhibitors and implicate GGTase as a potential therapeutic target for Wnt-activated cancers.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / metabolism
  • Animals
  • Dose-Response Relationship, Drug
  • Eye / drug effects
  • Eye / growth & development
  • Leucine / analogs & derivatives*
  • Leucine / chemistry
  • Leucine / pharmacology
  • Molecular Structure
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway / drug effects*
  • Zebrafish / anatomy & histology
  • Zebrafish / genetics
  • Zebrafish / metabolism*
  • beta Catenin / metabolism*

Substances

  • GGTI 286
  • Small Molecule Libraries
  • Wnt Proteins
  • beta Catenin
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • Leucine