Discovery of tert-amine-based RORγt agonists.
Eur J Med Chem
; 224: 113704, 2021 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-34303081
ABSTRACT
The nuclear receptor retinoic acid receptor-related orphan receptor gamma-t (RORγt) is a transcription factor regulating Th17 cell differentiation and proliferation from naive CD4+ T cells. Since Th17 cells have demonstrated the antitumor efficacy by eliciting remarkable activation of CD8+ T cells, RORγt agonists could be applied as potential small molecule therapeutics for cancer immunotherapy. Based on the previously reported RORγt agonist 1 and its resolved co-crystal structure, a series of new tertiary amines were designed, synthesized and biologically evaluated, yielding optimal moieties with improved chemical properties and biological responses. The combination of these optimal moieties resulted in identification of novel RORγt agonists such as 8b with further elevated RORγt agonism responses at a target-based level as well as in cell-based assays, which provided some structural knowledge for further optimization of RORγt agonists as small molecule therapeutics for cancer immunotherapy.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Descoberta de Drogas
/
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares
/
Aminas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China