Fiche publication
Date publication
juillet 2025
Journal
Journal of natural products
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROCHEL-GUIBERTEAU Natacha
Tous les auteurs :
Schwarz PF, Perhal AF, Guder F, Hernández González JE, Janssen K, Sağıroğlu E, Tahir A, Kirchmair J, Rochel N, Dirsch VM, Chen Y
Lien Pubmed
Résumé
Targeting retinoic acid-related orphan receptor γ (RORγ) with inverse agonists presents a promising therapeutic strategy for treating autoimmune diseases, including psoriasis, rheumatoid arthritis, and multiple sclerosis. Through structure-based virtual screening, we identified a lupane-type pentacyclic triterpenoid, (2Z)-2-(2-furanylmethylene)-3-oxolup-20(29)-en-28-oic acid (), as a new inverse agonist of RORγ. The compound exhibited IC values of 0.4 μM and 0.9 μM in Gal4-RORγ and full-length RORγ luciferase assays, respectively. Compound showed improved potency and efficacy compared to a structurally related known inverse agonist, betulinic acid. Among the four additional analogues tested (-), two ( and ) also demonstrated RORγ inverse agonist activity with low micromolar IC values in Gal4-RORγ luciferase assay. Real-time quantitative polymerase chain reaction experiments confirmed that compounds , , and downregulated RORγ target genes. Thermal shift assays showed that both betulinic acid and stabilized the RORγ ligand-binding domain. Molecular docking and structure-activity relationship analysis revealed distinct binding modes within the RORγ ligand-binding domains, further supported by site-directed mutagenesis. These findings expand the repertoire of RORγ inverse agonists based on the pentacyclic triterpenoid scaffolds.
Référence
J Nat Prod. 2025 07 28;:
