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PMID: 19383605 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled.

The Journal of biological chemistry ·Vol. 284 ·No. 24 ·2009-06-12 ·Pages 16256-16263

Grandy D, Shan J, Zhang X, Rao S, Akunuru S, Li H, Zhang Y, Alpatov I, Zhang XA, Lang RA, Shi DL, Zheng JJ

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/antagonists & inhibitors,chemistry,metabolism Animals Apoptosis/drug effects,physiology Benzoates/chemistry,pharmacology Cell Division/drug effects,physiology Cell Line, Tumor Cell Membrane/metabolism Crystallography Dishevelled Proteins Female Male Nuclear Magnetic Resonance, Biomolecular Oocytes/physiology PDZ Domains/physiology Phosphoproteins/antagonists & inhibitors,chemistry,metabolism Prostatic Neoplasms/drug therapy,pathology Signal Transduction/drug effects,physiology Wnt Proteins/antagonists & inhibitors,metabolism Xenopus Proteins Xenopus laevis
Chemicals
Adaptor Proteins, Signal Transducing Benzoates DVL1 protein, Xenopus Dishevelled Proteins Phosphoproteins Wnt Proteins Xenopus Proteins compound 3289-5066 compound 3289-8625
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Grandy David
From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Shan Jufang
From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Interdisciplinary Graduate Program, Memphis, Tennessee 38163.
Zhang Xinxin
From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Rao Sujata
Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
Akunuru Shailaja
Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
Li Hongyan
Laboratoire de Biologie du Dévelopement, CNRS UMR 7622, University Pierre et Marie Curie, 9 Quai Saint-Bernard, 75005 Paris, France.
Zhang Yanhui
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Alpatov Ivan
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Zhang Xin A
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Lang Richard A
Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
Shi De-Li
Laboratoire de Biologie du Dévelopement, CNRS UMR 7622, University Pierre et Marie Curie, 9 Quai Saint-Bernard, 75005 Paris, France.
Zheng Jie J
From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Department of Molecular Sciences, Memphis, Tennessee 38163. Electronic address: jie.zheng@stjude.org.
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M109.009647
Email
jie.zheng@stjude.org
Published
2009-06-12
Epub
2009-00-21
Pages
16256-16263
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2713547
Subset
IM
Grants
NIGMS NIH HHS · R01 GM081492-03 · United States
NCI NIH HHS · R25 CA023944 · United States
NIGMS NIH HHS · R01 GM081492 · United States
NIGMS NIH HHS · R01GM081492 · United States
NIGMS NIH HHS · R01 GM081492-02 · United States
External Links
PubMed source DOI: 10.1074/jbc.M109.009647 PMC Full Text View journal details
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