Novel aminotetrazole derivatives as selective STAT3 non-peptide inhibitors.
Eur J Med Chem
; 103: 163-74, 2015 Oct 20.
Article
de En
| MEDLINE
| ID: mdl-26352675
ABSTRACT
The development of inhibitors blocking STAT3 transcriptional activity is a promising therapeutic approach against cancer and inflammatory diseases. In this context, the selectivity of inhibitors against the STAT1 transcription factor is crucial as STAT3 and STAT1 play opposite roles in the apoptosis of tumor cells and polarization of the immune response. A structure-based virtual screening followed by a luciferase-containing promoter assay on STAT3 and STAT1 signaling were used to identify a selective STAT3 inhibitor. An important role of the aminotetrazole group in modulating STAT3 and STAT1 inhibitory activities has been established. Optimization of the hit compound leads to 23. This compound inhibits growth and survival of cells with STAT3 signaling pathway while displaying a minimal effect on STAT1 signaling. Moreover, it prevents lymphocyte T polarization into Th17 and Treg without affecting their differentiation into Th1 lymphocyte.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tétrazoles
/
Facteur de transcription STAT-3
/
Antinéoplasiques
Type d'étude:
Prognostic_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Eur J Med Chem
Année:
2015
Type de document:
Article