2. Academic Validation
  3. Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled

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

  • J Biol Chem. 2009 Jun 12;284(24):16256-16263. doi: 10.1074/jbc.M109.009647.
David Grandy 1,  Jufang Shan 2,  Xinxin Zhang 1,  Sujata Rao 3,  Shailaja Akunuru 3,  Hongyan Li 4,  Yanhui Zhang 5,  Ivan Alpatov 5,  Xin A Zhang 5,  Richard A Lang 3,  De-Li Shi 4,  Jie J Zheng 6
Affiliations

Affiliations

  • 1 From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
  • 2 From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Interdisciplinary Graduate Program, Memphis, Tennessee 38163.
  • 3 Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
  • 4 Laboratoire de Biologie du Dévelopement, CNRS UMR 7622, University Pierre et Marie Curie, 9 Quai Saint-Bernard, 75005 Paris, France.
  • 5 Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
  • 6 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.
PMID: 19383605 DOI: 10.1074/jbc.M109.009647
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-102067
    Dishevelled Protein PDZ Domain Inhibitor
    Wnt