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Investigation of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-diones as small molecule antagonists of ?-catenin/TCF transcription.

ABSTRACT: Nearly all colorectal cancers (CRCs) and varied subsets of other cancers have somatic mutations leading to ?-catenin stabilization and increased ?-catenin/TCF transcriptional activity. Inhibition of stabilized ?-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 ?-catenin/TCF transcriptional activity. We used xanthothricin, a known ?-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/?-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 ?-catenin stabilization by Wnt-3a ligand treatment. Two previously reported ?-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 ?-catenin transcriptional activity by degrading ?-catenin via a proteasome-dependent, but GSK3?-, APC-, AXIN2- and ?TrCP-independent, pathway. The data indicate the compounds act at the level of ?-catenin to inhibit Wnt/?-catenin/TCF function and highlight a robust strategy for assessing the activity of ?-catenin/TCF antagonists.

SUBMITTER: Zeller J 

PROVIDER: S-EPMC3896216 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Investigation of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-diones as small molecule antagonists of β-catenin/TCF transcription.

Zeller Jörg J   Turbiak Anjanette J AJ   Powelson Ian A IA   Lee Surin S   Sun Duxin D   Showalter H D Hollis HD   Fearon Eric R ER  

Bioorganic & medicinal chemistry letters 20130907 21

Nearly all colorectal cancers (CRCs) and varied subsets of other cancers have somatic mutations leading to β-catenin stabilization and increased β-catenin/TCF transcriptional activity. Inhibition of stabilized β-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 β-catenin/TCF transcriptional activity. We used xanthothricin, a known β-catenin/TCF antagonist of  ...[more]

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