Janus kinase-signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge[1]. JAK are a group of molecules, composed of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), which are key components within the JAK-signal transducers and activators of transcription pathway, where cytokine receptor signaling takes place. These molecules play a foundational role in the underlying pathogenesis of multiple immune-related conditions such as atopic dermatitis (AD), rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, and others[2]. The JAK/STAT signaling pathway is an universally expressed intracellular signal transduction pathway and involved in many crucial biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation. It provides a direct mechanism for extracellular factors-regulated gene expression[3]. In skeletal muscle, activation of the JAK/STAT pathway by the IL-6 cytokines accounts for opposite effects: on the one hand, it promotes muscle hypertrophy, by increasing the proliferation of satellite cells; on the other hand, it contributes to muscle wasting. The expression of IL-6 and of key members of the JAK/STAT pathway is regulated at the epigenetic level through histone methylation and histone acetylation mechanisms[4].GDC046 (Compound 3) was an effective and selective oral biouse inhibitor of TYK2, with Ki values of 4.8 nM, 83.8 nM, 27.6 nM and 253 nM against TYK2, JAK1, JAK2 and JAK3, respectively[5].
搜索
