ZFIN ID: ZDB-PUB-140513-245
A Zebrafish Chemical Suppressor Screening Identifies Small Molecule Inhibitors of the Wnt/beta-catenin Pathway
Nishiya, N., Oku, Y., Kumagai, Y., Sato, Y., Yamaguchi, E., Sasaki, A., Shoji, M., Ohnishi, Y., Okamoto, H., Uehara, Y.
Date: 2014
Source: Chemistry & Biology 21: 530-40 (Journal)
Registered Authors: Nishiya, Naoyuki, Okamoto, Hitoshi, Sato, Yuki
Keywords: none
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*
PubMed: 24684907 Full text @ Chem. Biol.
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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.

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