Evaluation of a chemical library of small-molecule Dishevelled antagonists that suppress tumor growth by down-regulating T-cell factor-mediated transcription.
We describe the rational generation of small-molecule agents that suppress tumor cell growth by down-regulating canonical Wnt signaling. We first produced a chemical library of the derivatives of indole-2-ketones and carbinols; we then screened them by using scalable assays of biochemical antagonism of Dishevelled-1 PDZ domain interactions and cell-based assays of Dishevelled-1-driven T-cell factor-mediated transcription. Compounds showing parallel effects in these assays were tested for selective induction of apoptosis in cancer cells. A new compound (24) that met the criteria for high biochemical antagonism, T-cell factor-mediated transcription, and induction of tumor-selective apoptosis was found to significantly suppress the growth of tumor xenografts in mice.
You
Liang
L
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
Xu
Zhidong
Z
Punchihewa
Chandanamali
C
Jablons
David M
DM
Fujii
Naoaki
N
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000072261:Dishevelled Proteins; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051820:TCF Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; D010750:Phosphoproteins; D054852:Small Molecule Libraries; D051820:TCF Transcription Factors; D053148:Caspase 3; D053179:Caspase 7