Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors.
J Med Chem
; 61(12): 5235-5244, 2018 06 28.
Article
em En
| MEDLINE
| ID: mdl-29856615
ABSTRACT
Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays â¼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
/
Janus Quinase 1
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article