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.
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
Liang
L
You
Zhidong
Z
Xu
Chandanamali
C
Punchihewa
David M
DM
Jablons
Naoaki
N
Fujii
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