Biochemical Properties of TAK-828F, a Potent and Selective Retinoid-Related Orphan Receptor Gamma t Inverse Agonist.
Pharmacology
; 102(5-6): 244-252, 2018.
Article
en En
| MEDLINE
| ID: mdl-30134246
BACKGROUND/AIMS: Retinoid-related orphan receptor gamma t (RORγt) is a master regulator of T helper 17 cells that plays a pivotal role in the production of inflammatory cytokines including interleukin (IL)-17. Therefore, RORγt has attracted much attention as a target receptor for the treatment of inflammatory diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, and psoriasis. This study aims to characterize TAK-828F, a potent and selective RORγt inverse agonist. METHODS: The biochemical properties of TAK-828F were evaluated using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assay, surface plasmon resonance (SPR) biosensor assay, cofactor recruitment assay, reporter assay, and IL-17 expression assay. RESULTS: TR-FRET binding assay and SPR biosensor assay revealed rapid, reversible, and high affinity binding of TAK-828F to RORγt. The cofactor recruitment assay showed that TAK-828F inhibited the recruitment of steroid receptor coactivator-1 to RORγt. Furthermore, TAK-828F inhibited the transcriptional activity of human and mouse RORγt with selectivity against human RORα and RORß. TAK-828F also suppressed IL-17 production in Jurkat cells, overexpressing human RORγt. CONCLUSION: These favorable properties will be of advantage in the evaluation of TAK-828F in clinical studies for inflammatory diseases. Furthermore, these findings demonstrate that TAK-828F could serve as a pharmacological tool for further studies of RORγt and inflammatory diseases.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sulfonas
/
Benzofuranos
/
Receptores Nucleares Huérfanos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Pharmacology
Año:
2018
Tipo del documento:
Article
Pais de publicación:
Suiza