PUBLICATION
Synthesis and biological evaluation of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines as new inhibitors of the Wnt/β-catenin signaling
- Authors
- Cosimelli, B., Laneri, S., Ostacolo, C., Sacchi, A., Severi, E., Porcù, E., Rampazzo, E., Moro, E., Basso, G., Viola, G.
- ID
- ZDB-PUB-140621-1
- Date
- 2014
- Source
- European Journal of Medicinal Chemistry 83C: 45-56 (Journal)
- Registered Authors
- Moro, Enrico
- Keywords
- Colorectal cancer, Imidazo[1,2-a]pyridines, Imidazo[1,2-a]pyrimidines, Signal transduction, Wnt signaling, β-catenin
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Chemistry Techniques, Synthetic
- Cyclin B1/metabolism
- Cyclin D1/metabolism
- Glycogen Synthase Kinase 3/metabolism
- Humans
- Inhibitory Concentration 50
- Proto-Oncogene Proteins c-myc/metabolism
- Pyridines/chemical synthesis*
- Pyridines/chemistry
- Pyridines/pharmacology*
- Pyrimidines/chemical synthesis*
- Pyrimidines/chemistry
- Pyrimidines/pharmacology*
- Transcription, Genetic/drug effects
- Wnt Signaling Pathway/drug effects*
- Zebrafish
- beta Catenin/genetics
- beta Catenin/metabolism*
- PubMed
- 24950489 Full text @ Eur. J. Med. Chem.
Citation
Cosimelli, B., Laneri, S., Ostacolo, C., Sacchi, A., Severi, E., Porcù, E., Rampazzo, E., Moro, E., Basso, G., Viola, G. (2014) Synthesis and biological evaluation of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines as new inhibitors of the Wnt/β-catenin signaling. European Journal of Medicinal Chemistry. 83C:45-56.
Abstract
Wnt/β-catenin signaling plays an important role in the regulation of embryonic development and tumorigenesis. Since its deregulation results in severe human diseases, especially cancer, the Wnt signaling pathway constitutes a promising platform for pharmacological targeting of cancer. In this study we synthesized a series of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines and identified some derivatives that were able to inhibit the Wnt/β-catenin signaling pathway in a luciferase reporter assay and cell proliferation in selected cancer cell lines, endowed with APC or β-catenin gene mutations. The most active compounds significantly downregulate the expression of Wnt target genes such as c-myc and cyclin D1. Further studies indicated that these compounds function independently of GSK-3β activity. More importantly, in vivo experiments, carried out on a Wnt-reporter zebrafish model indicate, in particular for compounds 4c and 4i as the most active compounds, an activity comparable to that of the reference compound IWR1, suggesting their potential use not only as small molecule inhibitors of the Wnt/β-catenin signal in Wnt driven cancers, but also in other Wnt-related diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping