Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors.
J Med Chem
; 61(23): 10665-10699, 2018 12 13.
Article
em En
| MEDLINE
| ID: mdl-30423248
ABSTRACT
Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cianamida
/
Inibidores de Proteínas Quinases
/
Janus Quinase 3
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article