原创力文档discovery of novel small molecule activators of β-catenin signaling发现新型小分子催化剂β-catenin信号.pdfVIP
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discovery of novel small molecule activators of β-catenin signaling发现新型小分子催化剂β-catenin信号
Discovery of Novel Small Molecule Activators of
b-Catenin Signaling
1,2 3 2 1
Folkert Verkaar , Mario van der Stelt , W. Matthijs Blankesteijn , Antoon A. van der Doelen , Guido J. R.
Zaman1*
1 Department of Molecular Pharmacology, Merck Research Laboratories, Oss, The Netherlands, 2 Department of Pharmacology and Toxicology, Maastricht University,
Maastricht, The Netherlands, 3 Department of Medicinal Chemistry, Merck Research Laboratories, Oss, The Netherlands
Abstract
Wnt/b-catenin signaling plays a major role in embryonic development and adult stem cell maintenance. Reduced activation
of the Wnt/b-catenin pathway underlies neurodegenerative disorders and aberrations in bone formation. Screening of a
small molecule compound library with a b-galactosidase fragment complementation assay measuring b-catenin nuclear
entry revealed bona fide activators of b-catenin signaling. The compounds stabilized cytoplasmic b-catenin and activated b–
catenin-dependent reporter gene activity. Although the mechanism through which the compounds activate b-catenin
signaling has yet to be determined, several key regulators of Wnt/b-catenin signaling, including glycogen synthase kinase 3
and Frizzled receptors, were excluded as the molecular target. The compounds displayed remarkable selectivity, as they
only induced b-catenin signaling in a human osteosarcoma U2OS cell line and not in a variety of other cell lines examined.
Our data indicate that differences in cellular Wnt/b-catenin signaling machinery can be exploited to identify cell type-
specific activators of Wnt/b-catenin signaling.
Citation: Verkaar F, van der Stelt M, Blankesteijn WM, van der Doelen AA, Zaman GJR (2011) Discovery of
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