PUBLICATION
Characterization and development of novel small-molecules inhibiting GSK3 and activating Wnt signaling
- Authors
- Zhong, H., Zou, H., Semenov, M.V., Moshinsky, D., He, X., Huang, H., Li, S., Quan, J., Yang, Z., and Lin, S.
- ID
- ZDB-PUB-091023-38
- Date
- 2009
- Source
- Molecular Biosystems 5(11): 1356-1360 (Journal)
- Registered Authors
- Huang, Haigen, Lin, Shuo, Zhong, Hanbing
- Keywords
- none
- MeSH Terms
-
- Animals
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/drug effects*
- Enzyme Inhibitors/pharmacology*
- Glycogen Synthase Kinase 3/antagonists & inhibitors*
- In Situ Hybridization
- Signal Transduction/drug effects*
- Wnt Proteins/metabolism*
- Zebrafish
- PubMed
- 19823752 Full text @ Mol. Biosyst.
Citation
Zhong, H., Zou, H., Semenov, M.V., Moshinsky, D., He, X., Huang, H., Li, S., Quan, J., Yang, Z., and Lin, S. (2009) Characterization and development of novel small-molecules inhibiting GSK3 and activating Wnt signaling. Molecular Biosystems. 5(11):1356-1360.
Abstract
Glycogen synthase kinase 3 (GSK3) is an essential component of the Wnt signaling pathway and plays important roles in regulating cell proliferation, differentiation, and apoptosis. As GSK3 is abnormally upregulated in several diseases including type II diabetes, Alzheimer's disease and cancer, it has been regarded as a potential drug target. During zebrafish development, inhibition of GSK3 leads to ectopic activation of the Wnt pathway, resulting in a headless embryo. Using this phenotype as an assay we screened a chemical library of 4000 compounds and identified one novel compound, 3F8, which specifically inhibits eye and forebrain formation in zebrafish embryos, resembling a typical Wnt overexpression phenotype. Cell reporter assays, chemical informatics analysis and in vitro kinase experiments revealed that 3F8 is a selective GSK3 inhibitor, which is more potent than SB216763, a commonly used GSK3 inhibitor. Based on the structure of 3F8, a new generation of compounds inhibiting GSK3 was synthesized and validated by biological assays. Together, 3F8 and its derivatives could be useful as new reagents and potential therapeutic candidates for GSK3 related diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping