IndraLab
Statements
Tofacitinib inhibits JAK1. 162 / 164
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eidos
"Tofacitinib inhibits JAK1 and JAK2 to a greater degree than was initially thought and also inhibits Tyk2 marginally.139 , 140 , 141 , 142 , 143 , 144 Experimental Experience Tofacitinib is the most potent ( inhibitory potency of 1 nM ) and selective JAK3 inhibitor developed to date ."
| PMC
reach
"To illustrate the difficulties with direct comparison of these methods, in vitro kinase assays demonstrate that tofacitinib is a potent inhibitor of JAK1 and JAK3, but that it is less active against JAK2 and TYK2, whereas baricitinib is a selective JAK1 and JAK2 inhibitor, and upadacitinib and filgotinib are selective JAK1 inhibitors8–10."
reach
"Therefore, it is likely that JAK inhibitors such as tofacitinib (a selective inhibitor of JAK1 and 3) and baricitinib (a selective inhibitor of JAK1 and 2) interupt the intracellular signaling of IL-20R ligands as well as the signaling of other members of the type I/II cytokine family (Table 1) (76)."
reach
"Current Food and Drug Administration (FDA) and European Medical Agency (EMA) licensed JAK inhibitors include two first-generation agents [11]; i) tofacitinib which inhibits JAK3 and JAK1 with some affinity for JAK2 and limited affinity for TYK2 and was licensed in 2012, and ii) baricitinib which inhibits JAK1 and JAK2 (and to a much lesser extent TYK2) and was licensed in 2017."
eidos
"The first generation JAKi encompasses baricitinib , which inhibits JAK1 and JAK2 , and tofacitinib , which inhibits JAK1 , JAK2 , JAK3 and , to a lesser extent , TYK2 [ 82 ] ; the second generation JAKi , includes , instead , upadacitinib , decernotinib , filgotinib , peficitinib and itacitinib , most of which are still under development ."
reach
"As the first generation of pan-JAK inhibitors, tofacitinib primarily suppressed JAK1/JAK3, disturbed the JAK–signal transducer and activator of transcription (STAT) pathway downstream of inflammatory cytokine receptors, and blocked most inflammatory cytokines, including IL-6 and the subsequent inflammatory storm (
Figure 2
) (29–31)."
reach
"Tofacitinib is a potent inhibitor of JAK1 and JAK3 with only moderate potency for JAK2 in in vitro assays, 6 and JAK1/3 inhibition by tofacitinib is proposed to block signaling for several cytokines integral to lymphocyte activation, proliferation, and function, including interleukin-2, -4, -7, -9, -15, and -21."
reach
"For patients with much larger duplications including the IL2RA locus it is difficult to assess whether IBD would have been reported relative to their other severe complaints and, if so, whether genetic changes in the large numbers of other duplicated genes would compensate for functional changes in the IL2RA locus.Although steroids and immunomodulators are still widely used in the treatment of IBD, small molecule inhibitors such as tofacitinib that specifically inhibit the JAK1 and JAK3 pathways are now becoming available."
reach
"The kinase inhibitor Tofacitinib (Tofa), a small molecule that preferentially blocks JAK1 activity, was administered in a clinically relevant regimen to mimic the human exposure, at doses that largely block phospho-Stat1 activation by IFN, alone or prior to a 2-hr parenteral IFN challenge."
eidos
"Tofacitinib primarily inhibits JAK1 and JAK3 and is an FDA-approved treatment for RA , with clinical trials ongoing for IBD [ 201 ] ; ruxolitinib is selective for JAK1 and JAK2 , and is approved for myelofibrosis and polycythaemia vera [ 202 ] ; and parcritinib is a JAK2 inhibitor which is currently in phase II trials for myelofibrosis [ 204 ] ."
reach
"To illustrate the difficulties with direct comparison of these methods, in vitro kinase assays demonstrate that tofacitinib is a potent inhibitor of JAK1 and JAK3, but that it is less active against JAK2 and TYK2, whereas baricitinib is a selective JAK1 and JAK2 inhibitor, and upadacitinib and filgotinib are selective JAK1 inhibitors [8] [9] [10] ."
reach
"Tofacitinib, which primarily inhibits JAK-3 and JAK-1 and, to a lesser extent, JAK-2, was shown to be effective in RA patients with inadequate responses to methotrexate (MTX) and anti-tumor necrosis factor (anti-TNF) agents as well as in MTX-naive RA patients 4, 5, 6, 7, as was baricitinib, a JAK-1/2 inhibitor 8, 9."
reach
"38 Notably, in spite of the (partially) distinct pharmacodynamic effects of the two compounds (ie, tofacitinib predominantly inhibiting JAK1 and JAK3, baricitinib predominantly inhibiting JAK1 and JAK2), their safety profile is very similar, suggesting that the actual in vivo effects might not be predicted entirely by in vitro " selectivity " assays."
reach
"XREF_BIBR Consequently, the immunomodulatory mechanisms of JAK1 and JAK3 inhibition by tofacitinib are expected to block or attenuate T-cell function, T-cell differentiation and cytokine signalling (e.g. IL-6, IL-21, IL-23, IFN-gamma), which play a key role in the pathogenesis of psoriasis."
eidos
"Tofacitinib , a Janus kinase ( JAK ) inhibitor targeting JAK3 and JAK1 , has been shown to suppress tissue-resident memory T cells and inhibit core effector pathways in an animal model in which human arteries were engrafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with GCA [ 90 ] ."
reach
"Tofacitinib is a potent inhibitor of JAK1 and JAK3 and currently approved for the treatment of rheumatoid arthritis (RA), has demonstrated effectiveness in the treatment of psoriasis in phase III clinical trials, and is currently tested as immunomodulator for organ transplantation [XREF_BIBR]."
reach
"However, clinical study data thus far available have established that the drug appears to have an acceptable safety profile, sufficient as to allow utilization and exploration across a range of immune mediated diseases, and the ability of tofacitinib to inhibit JAK1 and JAK2 may have improved tofacitinib 's efficacy in autoimmunity."
reach
"Ghoreschi et al. [XREF_BIBR, XREF_BIBR] reported that tofacitinib potently inhibited Jak3 and Jak1 and to a lesser extent Jak2 with little effects on Tyk2 and that it, thereby, inhibited signaling by interferon gamma (IFN-gamma), IL-6 and to a lesser extent IL-12 and IL-23, indicating that Th1 cell differentiation is therefore blocked, as is the generation of pathogenic Th17 cells."
reach
"106 These drugs differ in their specificity: upadacitinib is a selective JAK1 inhibitor, fedratinib targets JAK2, ruxolitinib and baricitinib inhibit JAK1 and JAK2, and tofacitinib inhibits JAK1, JAK2, and JAK3.106
107 Adverse reactions common to all JAK inhibitors include increased infections, cytopenias, and transaminitis."
eidos
"Jakinibs are small molecules that inhibit the signal transduction through JAK proteins : tofacitinib preferentially inhibits JAK1 and JAK3 , ruxolitinib and baricitinib inhibit JAK1 and JAK2 , and many other Jakinibs with different JAK specificity were recently discovered 157 , 158 ."
reach
"To illustrate the difficulties with direct comparison of these methods, in vitro kinase assays demonstrate that tofacitinib is a potent inhibitor of JAK1 and JAK3, but that it is less active against JAK2 and TYK2, whereas baricitinib is a selective JAK1 and JAK2 inhibitor, and upadacitinib and filgotinib are selective JAK1 inhibitors ."