title: Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled.
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.
authors.affiliation: From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: David
authors.initials: D
authors.lastname: Grandy
authors.affiliation: From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Interdisciplinary Graduate Program, Memphis, Tennessee 38163.
authors.forename: Jufang
authors.initials: J
authors.lastname: Shan
authors.affiliation: From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
authors.forename: Sujata
authors.initials: S
authors.lastname: Rao
authors.affiliation: Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Akunuru
authors.affiliation: Laboratoire de Biologie du Dévelopement, CNRS UMR 7622, University Pierre et Marie Curie, 9 Quai Saint-Bernard, 75005 Paris, France.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Ivan
authors.initials: I
authors.lastname: Alpatov
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Xin A
authors.initials: XA
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lang
authors.affiliation: Laboratoire de Biologie du Dévelopement, CNRS UMR 7622, University Pierre et Marie Curie, 9 Quai Saint-Bernard, 75005 Paris, France.
authors.forename: De-Li
authors.initials: DL
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Jie J
authors.initials: JJ
authors.lastname: Zheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003461:Crystallography; D000072261:Dishevelled Proteins; D005260:Female; D008297:Male; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes / Q000502:physiology; D054731:PDZ Domains / Q000502:physiology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D029867:Xenopus Proteins; D014982:Xenopus laevis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001565:Benzoates; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; C542872:compound 3289-5066; C542873:compound 3289-8625