Targeting the Janus kinases in rheumatoid arthritis: focus on tofacitinib

Yamaoka, Kunihiro; Tanaka, Yoshiya

doi:10.1517/14656566.2014.854771

Cited by 19 publications

(9 citation statements)

References 45 publications

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“…Despite that tofacitinib was initially described as a selective JAK3 inhibitor with 20-and 100-fold less potency in JAK2 and JAK1, respectively (Changelian et al, 2003), the compound was later on reported as a pan-JAK inhibitor less potent in TYK2 (Jiang et al, 2008;Meyer et al, 2010;Yamaoka and Tanaka, 2014) in line with our results. Data obtained internally for ruxolitinib showed that the compound is a pan-JAK inhibitor potent also in TYK2.…”

Section: Discussionsupporting

confidence: 86%

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats

Calbet

Ramis

Calama

et al. 2019

J Pharmacol Exp Ther

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The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.

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Section: Discussionsupporting

confidence: 86%

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats

Calbet

Ramis

Calama

et al. 2019

J Pharmacol Exp Ther

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“…Tofacitinib was the first JAK3 inhibitor investigated in human trials and is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, with the potential for expansion to other inflammatory and autoimmune diseases . Tofacitinib is also under clinical investigation for psoriasis, inflammatory bowel disease and prevention of transplant rejection .…”

Section: Tofacitinib As Treatment For Alopecia Universalismentioning

confidence: 99%

“…45 Moreover, expression of JAK3 is believed to be limited to T-, B-, NK and mast cells, 49,54,56,57 thus a JAK3 deficiency may cause immunodeficiency, although its specificity prevents pleiotropic defects. 58 Tofacitinib was the first JAK3 inhibitor investigated in human trials 58 and is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, 59 with the potential for expansion to other inflammatory and autoimmune diseases. 60,61 Tofacitinib is also under clinical investigation for psoriasis, inflammatory bowel disease and prevention of transplant rejection.…”

Section: The Hair Follicle Is Immune-privileged Sitementioning

confidence: 99%

Efficacy of tofacitinib in treatment of alopecia universalis in two patients

Gupta

Carviel

Abramovits

2016

Acad Dermatol Venereol

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“…A number of TNF-α antagonists, such as infliximab, etanercept, adalimumab, golimumab and certolizumab pegol, have been developed and used in the treatment of RA 27 . The inhibitors of JAKs (e.g., tofacitinib and baricitinib) and spleen tyrosine kinase (SYK) (e.g., fostamatinib), have shown advantages in the interruption of kinase activities, thereby affecting intracellular signaling through kinase inhibition 54 . In this study, we identified a naturally sourced small molecule, NSM00191, that specifically disrupted the interaction between TRADD and TRAF2 (Figures 6 A, 6B and 6E), significantly reduced cell proliferation in vitro (Figure 6 D), and greatly improved inflammation status in RA mouse models (Figure 7 ).…”

Section: Discussionmentioning

confidence: 99%

The small molecule NSM00191 specifically represses the TNF-α/NF-кB axis in foot and ankle rheumatoid arthritis

Wen¹,

Chen²,

Liang³

et al. 2018

Int. J. Biol. Sci.

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The activation of TNF-α/NF-кB signaling is involved in the regulation of a wide range of biological processes, such as cell proliferation, differentiation and apoptosis, eventually causing a number of diseases, such as cancer and inflammation. Here, we found that TNF-α/NF-кB signaling was activated in a large number of blood samples taken from foot and ankle rheumatoid arthritis (RA) patients. By applying a microarray assay to the human synovial sarcoma cell line SW982 and the human fibroblast-like synoviocyte cell line HFLS-RA, as well as in their corresponding p65 knockdown and -overexpressing cells, we identified and verified the activation of many p65 targets, including cytokines (e.g., TNF-α and IL-6), chemokines (e.g., MCP-1 and PANTES), protein receptors (e.g., CD-40 and MHC-1), and inducible enzymes (e.g., COX2). In addition, we subjected microRNAs from foot and ankle RA patients to a microRNA-specific microarray and found that miR-7-5p targeted the 3'-UTR of p65, negatively regulating its expression. By applying an in vitro screen to identify small molecules that specifically inhibited the interaction between TRADD and TNFR2, we found that NSM00191 strongly inhibited the activation of TNF-α/NF-кB signaling in vitro and in vivo, causing the downregulation of NF-кB targets and the decrease of arthritis scores. Collectively, our findings shed new light on the regulation of the TNF-α/NF-кB axis and might provide a new avenue for RA treatment.

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Targeting the Janus kinases in rheumatoid arthritis: focus on tofacitinib

Cited by 19 publications

References 45 publications

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats

Efficacy of tofacitinib in treatment of alopecia universalis in two patients

The small molecule NSM00191 specifically represses the TNF-α/NF-кB axis in foot and ankle rheumatoid arthritis

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