A novel JAK inhibitor JTE‐052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents

Abstract

Janus kinases (JAKs) are required for several inflammatory cytokine signalling pathways and are implicated in the pathogenesis of chronic dermatitis, including atopic dermatitis and psoriasis. JAK inhibitors are therefore promising therapeutic candidates for chronic dermatitis. In this study, we evaluated the effects of the novel JAK inhibitor JTE-052 on inflammatory responses associated with chronic dermatitis, and compared its profile with those of conventional therapeutic agents in rodent models of chronic dermatitis. JTE-052 inhibited the Th1-, Th2-and Th17-type inflammatory responses of human T cells and mast cells in vitro. Oral administration of JTE-052 inhibited skin inflammation in hapten-induced chronic dermatitis in mice, associated with reduced levels of inflammatory cytokines in the skin and immunoglobulin (Ig) E in serum. In contrast, although ciclosporin partly inhibited skin inflammation, it did not reduce interleukin (IL)-4 production in skin, and enhanced IgE production in serum.Oral administration of JTE-052 also inhibited skin inflammation in mouse models of atopic dermatitis and psoriasis induced by a mite extract, thymic stromal lymphopoietin or IL-23. The maximal efficacy of JTE-052 in these dermatitis models was superior to the conventional therapeutic agents, ciclosporin and methotrexate. Topical application of JTE-052 ointment ameliorated hapten-induced chronic dermatitis in rats more effectively than tacrolimus ointment. Furthermore, JTE-052 ointment did not cause the thinning of normal skin associated with topical corticosteroids. These results indicate that JTE-052 is a promising candidate as an anti-inflammatory drug for various types of chronic dermatitis, with a distinctly different profile from conventional therapy following either oral or topical application. K E Y W O R D Satopic dermatitis, corticosteroids, cytokine signalling, immunosuppressants, psoriasisThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study

“…JTE‐052 has been shown to inhibit the JAK1, JAK2, JAK3 and tyrosine kinase 2 enzymes in enzymatic assays . JTE‐052 has also been shown to inhibit the activation of inflammatory cells such as T cells, B cells, monocytes and mast cells in vitro , and to suppress skin inflammation in animal dermatitis models . Additionally, JTE‐052 improves the skin barrier dysfunction by promoting the production of keratinocyte proteins including filaggrin, and suppresses pruritus induced by IL‐31 .…”

“…14 JTE-052 has also been shown to inhibit the activation of inflammatory cells such as T cells, B cells, monocytes and mast cells in vitro, 14 and to suppress skin inflammation in animal dermatitis models. 15 Additionally, JTE-052 improves the skin barrier dysfunction by promoting the production of keratinocyte proteins including filaggrin, 16 and suppresses pruritus induced by IL-31. 17 Consequently, topical JTE-052 is expected to be a novel drug for the treatment of AD, suppressing inflammation and pruritus, as well as restoring skin barrier function.…”

Phase 1 studies to assess the safety, tolerability and pharmacokinetics of JTE‐052 (a novel Janus kinase inhibitor) ointment in Japanese healthy volunteers and patients with atopic dermatitis

“…JTE‐052 potently inhibited all of the JAK subtypes with half maximal inhibitory concentration values of 2.8 ± 0.6, 2.6 ± 0.2, 13 ± 0 and 58 ± 9 nmol/L for JAK1, JAK2, JAK3 and Tyk2, respectively . JTE‐052 has been investigated to test its ability to inhibit the activation of inflammatory cells such as T cells, B cells, monocytes and mast cells in vitro , and to suppress skin inflammation in animal dermatitis models . Not only immunological abnormalities but also skin barrier dysfunction and pruritus have recently been recognized as major factors involved in the pathogenesis and progression of AD .…”

The oral Janus kinase/spleen tyrosine kinase inhibitorASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate‐to‐severe atopic dermatitis: results from a randomized double‐blind placebo‐controlled study

“…The JAK kinases family (JAK1, JAK2, JAK3 and TYK2) is also involved in signalling pathways of several cytokines involved in AD, such as IL‐4, IL‐13, IL‐31 and IL‐33 . In addition, JAK inhibitors, targeting mostly JAK1, have been shown to be effective for the treatment of AD . ASN002 is a potent, dual inhibitor of JAK and SYK kinases with inhibitory concentration (IC50) values of 5 nmol L −1 (SYK), 46 nmol L −1 (JAK1), 4 nmol L −1 (JAK2), 11 nmol L −1 (JAK3) and 8 nmol L −1 (TYK2) in biochemical assays .…”