化学
贾纳斯激酶
哮喘
药理学
STAT6
斯达
JAK-STAT信号通路
Janus激酶3
吸入
激酶
信号转导
体外
车站3
免疫学
酪氨酸激酶
生物化学
医学
白细胞介素12
转录因子
基因
细胞毒性T细胞
解剖
作者
Magnus Nilsson,Kristina Berggren,Susanne Berglund,Silvia Cerboni,Mia Collins,Stefan Geschwindner,D. Elmqvist,Neil P. Grimster,Ramon Hendrickx,Johan R. Johansson,Jason G. Kettle,Matti Lepistö,Magdalena Rhedin,Amir Smailagic,Qibin Su,Tiiu Wennberg,Allan Wu,Torben Østerlund,Thomas Naessens,Suman Mitra
标识
DOI:10.1021/acs.jmedchem.3c00554
摘要
JAK-STAT cytokines are critical in regulating immunity. Persistent activation of JAK-STAT signaling pathways by cytokines drives chronic inflammatory diseases such as asthma. Herein, we report on the discovery of a highly JAK1-selective, ATP-competitive series of inhibitors having a 1000-fold selectivity over other JAK family members and the approach used to identify compounds suitable for inhaled administration. Ultimately, compound 16 was selected as the clinical candidate, and upon dry powder inhalation, we could demonstrate a high local concentration in the lung as well as low plasma concentrations, suggesting no systemic JAK1 target engagement. Compound 16 has progressed into clinical trials. Using 16, we found JAK1 inhibition to be more efficacious than JAK3 inhibition in IL-4-driven Th2 asthma.
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