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

David Grandy, Jufang Shan, Xinxin Zhang, Sujata Rao, Shailaja Akunuru, Hongyan Li, Yanhui Zhang, Ivan Alpatov, Xin A. Zhang, Richard A. Lang, De Li Shi, Jie J. Zheng

    Research output: Contribution to journalArticle

    123 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)16256-16263
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume284
    Issue number24
    DOIs
    StatePublished - Jun 12 2009

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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  • Cite this

    Grandy, D., Shan, J., Zhang, X., Rao, S., Akunuru, S., Li, H., Zhang, Y., Alpatov, I., Zhang, X. A., Lang, R. A., Shi, D. L., & Zheng, J. J. (2009). Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. Journal of Biological Chemistry, 284(24), 16256-16263. https://doi.org/10.1074/jbc.M109.009647