4.4 Next generation JAK inhibitors
Unlike JAK1 and JAK2 inhibition impacts numerous cytokines and have widely effects on their functions, JAK3 and TYK2 are related to a smaller kind of cytokines. More selective JAK3 or TYK2 inhibition may be a strategy of the side effects beyond pan-JAK inhibitors. Even if there may cost an extent of efficacy. Up to now, two JAK3 inhibitors, decernotinib and PF-06651600, are in clinical trials study (treating RA, alopecia areata, CD, and UC). While theoretically blocking JAK3 should only inhibits γC related cytokinesis. However, decernotinib also shows affecting CYP3A4 thus influence metabolism of statins and other drugs(Zetterberg et al., 2016). Another strategy to decrease the affection of JAK2 dependent cytokines is JAK1 selective inhibitor. Five JAK1 selective inhibitors, filgotinib, upadacitinib (ABT-494), itacitinib, PF-04965842, GSK2586184, are in the stage of clinical trials. Additionally, restricted to targeting IL-12, IL-23, type I, and type III IFNs, TYK2(BMS-986165, PF-06700841) selective inhibitors have the superiority of utility in IBD and SLE with more partially side effects. Besides the selective JAK inhibitors, considering the complicated mechanism of many diseases, combined inhibitors such as cerdulatinib (targets SYK/JAK)(Coffey et al., 2014), pacritinib(targets JAK2/FLT3)(Hatzimichael, Tsolas & Briasoulis, 2014), with two or more target kinases may broader the usage in treating disease.
Furthermore, targeting JAK upstream suppressor kinases such as SOCS or downstream STATs including oligonucleotide-based STAT inhibitors, STAT-targeting small molecules, inhibitory peptides, and siRNAs(Miklossy, Hilliard & Turkson, 2013; Sen & Grandis, 2012) represent a new territory and their effects in ARDS remain to be convinced.