Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGFßRI).
Bioorg Med Chem
; 26(5): 1026-1034, 2018 03 01.
Article
de En
| MEDLINE
| ID: mdl-29422332
ABSTRACT
The TGFß-TGFßR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFßR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFßRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparentâ¯=â¯0.14â¯nM), long residence time (T1/2â¯>â¯120â¯min) and significantly improved potency in the PSMAD cellular assay (IC50â¯=â¯24â¯nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFß-stimulated phospho-SMAD was observed in primary human T cells.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Composés bicycliques pontés
/
Protein-Serine-Threonine Kinases
/
Récepteurs TGF-bêta
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
Bioorg Med Chem
Sujet du journal:
BIOQUIMICA
/
QUIMICA
Année:
2018
Type de document:
Article