Investigation of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-diones as small molecule antagonists of ¦Â-catenin/TCF transcription
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- 作者：J?rg Zeller ; Anjanette J. Turbiak ; Ian A. Powelson ; Surin Lee ; Duxin Sun ; H.D. Hollis Showalter ; Eric R. Fearon
- 关键词：Wnt signaling ; ¦Â-Catenin ; T-cell factor (TCF) ; Small molecule antagonists
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：1 November, 2013
- 年：2013
- 卷：23
- 期：21
- 页码：5814-5820
- 全文大小：1323 K
文摘
Nearly all colorectal cancers (CRCs) and varied subsets of other cancers have somatic mutations leading to ¦Â-catenin stabilization and increased ¦Â-catenin/TCF transcriptional activity. Inhibition of stabilized ¦Â-catenin in CRC cell lines arrests their growth and highlights the potential of this mechanism for novel cancer therapeutics. We have pursued efforts to develop small molecules that inhibit ¦Â-catenin/TCF transcriptional activity. We used xanthothricin, a known ¦Â-catenin/TCF antagonist of microbial origin, as a lead compound to synthesize related analogues with drug-like features such as low molecular weight and good metabolic stability. We studied a panel of six candidate Wnt/¦Â-catenin/Tcf-regulated genes and found that two of them (Axin2, Lgr5) were reproducibly activated (9-10 fold) in rat intestinal epithelial cells (IEC-6) following ¦Â-catenin stabilization by Wnt-3a ligand treatment. Two previously reported ¦Â-catenin/TCF antagonists (calphostin C, xanthothricin) and XAV939 (tankyrase antagonist) inhibited Wnt-activated genes in a dose-dependent fashion. We found that four of our compounds also potently inhibited Wnt-mediated activation in the panel of target genes. We investigated the mechanism of action for one of these (8c) and demonstrated these novel small molecules inhibit ¦Â-catenin transcriptional activity by degrading ¦Â-catenin via a proteasome-dependent, but GSK3¦Â-, APC-, AXIN2- and ¦ÂTrCP-independent, pathway. The data indicate the compounds act at the level of ¦Â-catenin to inhibit Wnt/¦Â-catenin/TCF function and highlight a robust strategy for assessing the activity of ¦Â-catenin/TCF antagonists.