Discovery and Characterization of a Small Molecule Inhibitor of the PDZ Domain of Dishevelled*
AUTOR(ES)
Grandy, David
FONTE
American Society for Biochemistry and Molecular Biology
RESUMO
Dishevelled (Dvl) is an essential protein in the Wnt signaling pathways; it uses its PDZ domain to transduce the Wnt signals from the membrane receptor Frizzled to downstream components. Here, we report identifying a drug-like small molecule compound through structure-based ligand screening and NMR spectroscopy and show the compound to interact at low micromolar affinity with the PDZ domain of Dvl. In a Xenopus testing system, the compound could permeate the cell membrane and block the Wnt signaling pathways. In addition, the compound inhibited Wnt signaling and reduced the levels of apoptosis in the hyaloid vessels of eye. Moreover, this compound also suppressed the growth of prostate cancer PC-3 cells. These biological effects suggest that by blocking the PDZ domain of Dvl, the compound identified in our studies effectively inhibits the Wnt signaling and thus provides a useful tool for studies dissecting the Wnt signaling pathways.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2713547Documentos Relacionados
- Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2
- Rational design and characterization of a Rac GTPase-specific small molecule inhibitor
- Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation
- Identification of a small molecule inhibitor of Sir2p
- A small-molecule inhibitor of the ribonucleolytic activity of human angiogenin that possesses antitumor activity