Journal
MOLECULAR CANCER THERAPEUTICS
Volume 7, Issue 6, Pages 1633-1638Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-08-0155
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Funding
- NCI NIH HHS [R01 CA093708, R01 CA 093708-01A3] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA093708] Funding Source: NIH RePORTER
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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.
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