A highly selective JAK3 inhibitor is developed for treating rheumatoid arthritis by suppressing γc cytokine-related JAK-STAT signal.

ABSTRACT: Janus kinases (JAKs) play a critical role in immune responses by relaying signals from more than 50 cytokines, making them attractive therapeutic targets for autoimmune diseases. Although approved JAK inhibitors have demonstrated clinical efficacy, they target a broad spectrum of cytokines, which results in side effects. Therefore, next-generation inhibitors maintain efficacy, while sparing adverse events need to be developed. Among members of the JAK family, JAK3 only regulates a narrow spectrum of γc cytokines and becomes a potentially ideal target. Here, a highly JAK3-selective inhibitor Z583 is developed, which showed a potent inhibition of JAK3 with an IC₅₀ of 0.1 nM and exhibited a 4500-fold selectivity for JAK3 than other JAK subtypes. Furthermore, Z583 completely inhibit

SUBMITTER: Chen C 

PROVIDER: S-EPMC9390995 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature