Characterization and development of novel small-molecules inhibiting GSK3 and activating Wnt signaling.
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.
Zhong
Hanbing
H
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen University Town, Shenzhen 518055, China. zhong@szpku.edu.cn
Zou
Haixia
H
Semenov
Mikhail V
MV
Moshinsky
Deborah
D
He
Xi
X
Huang
Haigen
H
Li
Song
S
Quan
Junmin
J
Yang
Zhen
Z
Lin
Shuo
S
D000818:Animals; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D017403:In Situ Hybridization; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish
D004791:Enzyme Inhibitors; D051153:Wnt Proteins; D038362:Glycogen Synthase Kinase 3