Investigation of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-diones as small molecule antagonists of β-catenin/TCF transcription
| Autor: | H. D. Hollis Showalter, Anjanette J. Turbiak, Duxin Sun, Surin Lee, Eric R. Fearon, Ian A. Powelson, Jörg Zeller |
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| Rok vydání: | 2013 |
| Předmět: |
Transcriptional Activation
Beta-catenin Clinical Biochemistry Pharmaceutical Science TCF/LEF family Biochemistry Article Cell Line Small Molecule Libraries chemistry.chemical_compound Drug Discovery medicine AXIN2 Animals Wnt Signaling Pathway Molecular Biology beta Catenin biology Triazines Chemistry Organic Chemistry Wnt signaling pathway Epithelial Cells Small molecule Molecular biology Rats Calphostin C Mechanism of action Catenin biology.protein Molecular Medicine medicine.symptom TCF Transcription Factors |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:5814-5820 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2013.08.111 |
| Popis: | 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 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/β-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 β-catenin stabilization by Wnt-3a ligand treatment. Two previously reported β-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 β-catenin transcriptional activity by degrading β-catenin via a proteasome-dependent, but GSK3β-, APC-, AXIN2- and βTrCP-independent, pathway. The data indicate the compounds act at the level of β-catenin to inhibit Wnt/β-catenin/TCF function and highlight a robust strategy for assessing the activity of β-catenin/TCF antagonists. |
| Databáze: | OpenAIRE |
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