Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain.
Proc Natl Acad Sci U S A
; 115(33): E7786-E7794, 2018 08 14.
Article
de En
| MEDLINE
| ID: mdl-30061414
ABSTRACT
The action of the collagen binding receptor tyrosine kinase (RTK) discoidin domain receptor 2 (DDR2) in both tumor and tumor stromal cells has been established as critical for breast cancer metastasis. Small molecule inhibitors that target the extracellular domain of RTKs are rare, as they have classically been regarded as too small to block binding with large polypeptide ligands. Here, we report the identification and characterization of a selective, extracellularly acting small molecule inhibitor (WRG-28) of DDR2 that uniquely inhibits receptor-ligand interactions via allosteric modulation of the receptor. By targeting DDR2, WRG-28 inhibits tumor invasion and migration, as well as tumor-supporting roles of the stroma, and inhibits metastatic breast tumor cell colonization in the lungs. These findings represent an approach to inhibiting tumor-stromal interactions and support the development of allosteric inhibitors of DDR2, such as WRG-28, as a promising approach to antimetastasis treatment.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs du sein
/
Transduction du signal
/
Inhibiteurs de protéines kinases
/
Microenvironnement tumoral
/
Récepteur-2 à domaine discoïdine
/
Protéines tumorales
/
Antinéoplasiques
Type d'étude:
Prognostic_studies
Limites:
Animals
/
Female
/
Humans
Langue:
En
Journal:
Proc Natl Acad Sci U S A
Année:
2018
Type de document:
Article