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.

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.

• Authors: Barbara Cosimelli, Sonia Laneri, Carmine Ostacolo, Antonia Sacchi, Elda Severi, Elena Porcù, Elena Rampazzo, Enrico Moro, Giuseppe Basso, Giampietro Viola
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 83 Pg. 45-56 (Aug 18 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 24950489 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• Cyclin B1
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• Pyridines
• Pyrimidines
• beta Catenin
• Cyclin D1
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chemistry Techniques, Synthetic
• Cyclin B1 (metabolism)
• Cyclin D1 (metabolism)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Inhibitory Concentration 50
• Proto-Oncogene Proteins c-myc (metabolism)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Transcription, Genetic (drug effects)
• Wnt Signaling Pathway (drug effects)
• Zebrafish
• beta Catenin (genetics, metabolism)