Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled.
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.
Grandy
David
D
From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Shan
Jufang
J
From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Interdisciplinary Graduate Program, Memphis, Tennessee 38163.
Zhang
Xinxin
X
From the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Rao
Sujata
S
Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
Akunuru
Shailaja
S
Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
Li
Hongyan
H
Laboratoire de Biologie du Dévelopement, CNRS UMR 7622, University Pierre et Marie Curie, 9 Quai Saint-Bernard, 75005 Paris, France.
Zhang
Yanhui
Y
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Alpatov
Ivan
I
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Zhang
Xin A
XA
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Lang
Richard A
RA
Department of Ophthalmology and Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
Shi
De-Li
DL
Laboratoire de Biologie du Dévelopement, CNRS UMR 7622, University Pierre et Marie Curie, 9 Quai Saint-Bernard, 75005 Paris, France.
Zheng
Jie J
JJ
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.
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
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