An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth.
Recent progress in the development of inhibitors of protein-protein interactions has opened the door for developing drugs that act by novel and selective mechanisms. Building on that work, we designed a small-molecule inhibitor of the Wnt signaling pathway, which is aberrantly activated across a wide range of human tumors. The compound, named FJ9, disrupts the interaction between the Frizzed-7 Wnt receptor and the PDZ domain of Dishevelled, down-regulating canonical Wnt signaling and suppressing tumor cell growth. The antitumorigenic effects of FJ9 were pronounced, including induction of apoptosis in human cancer cell lines and tumor growth inhibition in a mouse xenograft model. FJ9 is thus among the first non-peptide inhibitors to show therapeutic efficacy through disruption of PDZ protein-protein interactions.
Fujii
Naoaki
N
Department of Pharmaceutical Chemistry, Thoracic Oncology Labratory, University of California San Francisco, and Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Naoaki.Fujii@stjude.org
You
Liang
L
Xu
Zhidong
Z
Uematsu
Kazutsugu
K
Shan
Jufang
J
He
Biao
B
Mikami
Iwao
I
Edmondson
Lillian R
LR
Neale
Geoffrey
G
Zheng
Jie
J
Guy
R Kiplin
RK
Jablons
David M
DM
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D000072261:Dishevelled Proteins; D005260:Female; D051157:Frizzled Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; C517169:FJ9 compound; C115810:FZD7 protein, human; D051157:Frizzled Receptors; D007211:Indoles; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D051176:beta Catenin