A novel CDK8 inhibitor with poly-substituted pyridine core: Discovery and anti-inflammatory activity evaluation in vivo.
Bioorg Chem
; 133: 106402, 2023 04.
Article
en En
| MEDLINE
| ID: mdl-36791618
ABSTRACT
As an ideal anti-inflammatory target, cyclin-dependent kinase 8 (CDK8) has gradually attracted the attention of researchers. CDK8 inhibition up-regulates Interleukin-10 (IL-10) expression by enhancing the transcriptional activity of activator protein-1 (AP-1), and augmenting IL-10 abundance is a viable strategy for the treatment of inflammatory bowel disease (IBD). In this research, through structure-based drug design and dominant fragment hybridization, a series of poly-substituted pyridine derivatives were designed and synthesized as CDK8 inhibitors. Ultimately, compound CR16 was identified as the best one, which exhibited good inhibitory activity against CDK8 (IC50 = 74.4 nM). In vitro and in vivo studies indicated that CR16 could enhance the transcriptional activity of AP-1, augment the abundance of IL-10, and affect CDK8-related signaling pathways including TLR7/NF-κB/MAPK and IL-10-JAK1-STAT3 pathways. In addition, CR16 showed potent therapeutic effect in an animal model of IBD.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Interleucina-10
/
Inhibidores de Proteínas Quinasas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Bioorg Chem
Año:
2023
Tipo del documento:
Article