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

118 Citations (Scopus)

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

Fingerprint

PDZ Domains
Wnt Signaling Pathway
Molecules
Frizzled Receptors
Xenopus
Prostatic Neoplasms
Magnetic Resonance Spectroscopy
Cell Membrane
Apoptosis
Ligands
Cell membranes
Membranes
Nuclear magnetic resonance spectroscopy
Growth
Screening
Pharmaceutical Preparations
Proteins
Testing

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Grandy, D., Shan, J., Zhang, X., Rao, S., Akunuru, S., Li, H., ... 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

Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. / Grandy, David; Shan, Jufang; Zhang, Xinxin; Rao, Sujata; Akunuru, Shailaja; Li, Hongyan; Zhang, Yanhui; Alpatov, Ivan; Zhang, Xin A.; Lang, Richard A.; Shi, De Li; Zheng, Jie J.

In: Journal of Biological Chemistry, Vol. 284, No. 24, 12.06.2009, p. 16256-16263.

Research output: Contribution to journalArticle

Grandy, D, Shan, J, Zhang, X, Rao, S, Akunuru, S, Li, H, Zhang, Y, Alpatov, I, Zhang, XA, Lang, RA, Shi, DL & Zheng, JJ 2009, 'Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled', Journal of Biological Chemistry, vol. 284, no. 24, pp. 16256-16263. https://doi.org/10.1074/jbc.M109.009647
Grandy, David ; Shan, Jufang ; Zhang, Xinxin ; Rao, Sujata ; Akunuru, Shailaja ; Li, Hongyan ; Zhang, Yanhui ; Alpatov, Ivan ; Zhang, Xin A. ; Lang, Richard A. ; Shi, De Li ; Zheng, Jie J. / Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 24. pp. 16256-16263.
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