Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
-
Adaptor Proteins, Signal Transducing / chemistry
-
Adaptor Proteins, Signal Transducing / metabolism
-
Animals
-
Apoptosis / drug effects
-
Apoptosis / physiology
-
Benzoates / chemistry
-
Benzoates / pharmacology*
-
Cell Division / drug effects
-
Cell Division / physiology
-
Cell Line, Tumor
-
Cell Membrane / metabolism
-
Crystallography
-
Dishevelled Proteins
-
Female
-
Male
-
Nuclear Magnetic Resonance, Biomolecular
-
Oocytes / physiology
-
PDZ Domains / physiology*
-
Phosphoproteins / antagonists & inhibitors*
-
Phosphoproteins / chemistry
-
Phosphoproteins / metabolism
-
Prostatic Neoplasms / drug therapy*
-
Prostatic Neoplasms / pathology
-
Signal Transduction / drug effects*
-
Signal Transduction / physiology
-
Wnt Proteins / antagonists & inhibitors
-
Wnt Proteins / metabolism*
-
Xenopus Proteins
-
Xenopus laevis
Substances
-
Adaptor Proteins, Signal Transducing
-
Benzoates
-
DVL1 protein, Xenopus
-
Dishevelled Proteins
-
Phosphoproteins
-
Wnt Proteins
-
Xenopus Proteins
-
compound 3289-5066
-
compound 3289-8625