Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. JAKs play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. Since members of the type I and type II cytokine receptor families possess no catalytic kinase activity, they rely on the JAK family of tyrosine kinases to phosphorylate and activate downstream proteins involved in their signal transduction pathways. The JAK autophosphorylation induces a conformational change within itself, enabling it to transduce the intracellular signal by further phosphorylating and activating transcription factors called STATs. The activated STATs dissociate from the receptor and form dimers before translocating to the cell nucleus, where they regulate transcription of selected genes. Transgenic mice that do not express JAK1 have defective responses to some cytokines, such as interferon-gamma. JAK1 and JAK2 play important roles in type II interferon (interferon-gamma) signalling, whereas JAK1 and TYK2 in type I interferon signalling. Mice that do not express TYK2 have defective natural killer cell function.
Peficitinib is a potent Janus kinase (JAK) inhibitor
Peficitinib (ASP015K) targets the JAK family of tyrosine kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2). JAK inhibitors are targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). JAKs transduce inflammatory cytokine signals from the cell membrane to the nucleus and are consequently implicated in the pathogenesis of rheumatoid arthritis. Therefore, Peficitinib has demonstrated efficacy and tolerability for rheumatoid arthritis. In vitro, Peficitinib inhibits IL-2-induced T cell proliferation in a concentration-dependent manner. Besides, Peficitinib inhibits IL-2-induced STAT5 phosphorylation in a concentration-dependent manner. In vivo, Peficitinib shows dose-dependent efficacy both in prophylactic and therapeutic dosing regimens in an adjuvant-induced arthritis rat model.
All in all, Peficitinib is a JAK inhibitor that has demonstrated efficacy and tolerability for rheumatoid arthritis.