Preclinical Evaluation of Local JAK1 and JAK2 Inhibition in Cutaneous Inflammation

Abstract

JAKs are required for signaling initiated by several cytokines (e.g., IL-4, IL-12, IL-23, thymic stromal lymphopoietin (TSLP), and IFNγ) implicated in the pathogenesis of inflammatory skin diseases such as psoriasis and atopic dermatitis (AD). Direct antagonism of cytokines, such as IL-12 and IL-23 using ustekinumab, has proven effective in randomized studies in psoriasis patients. We hypothesized that local inhibition of cytokine signaling using topical administration of INCB018424, a small molecule inhibitor of JAK1 and JAK2, would provide benefit similar to systemic cytokine neutralization. In cellular assays, INCB018424 inhibits cytokine-induced JAK/signal transducers and activators of transcription (STAT) signaling and the resultant production of inflammatory proteins (e.g., IL-17, monocyte chemotactic protein-1, and IL-22) in lymphocytes and monocytes, with half-maximal inhibitory concentration values <100 nM. In vivo, topical application of INCB018424 resulted in suppression of STAT3 phosphorylation, edema, lymphocyte infiltration, and keratinocyte proliferation in a murine contact hypersensitivity model and inhibited tissue inflammation induced by either intradermal IL-23 or TSLP. Topical INCB018424 was also well tolerated in a 28-day safety study in Gottingen minipigs. These results suggest that localized JAK1/JAK2 inhibition may be therapeutic in a range of inflammatory skin disorders such as psoriasis and AD. Clinical evaluation of topical INCB018424 is ongoing.

Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis

“…Corresponding to the scratching behavior results, topical application of each JAK inhibitor significantly inhibited the pruritogen-evoked cytokine secretions, including IL-31, TNFa, and TSLP, in the affected skin 30 minutes after TDI challenge. The antiinflammatory effects in allergic dermatitis by topical application of JAK inhibitors are also supported by the recently published study using topical application of the JAK1/JAK2 inhibitor ruxolitinib in a guinea pig model of delayed-type hypersensitivity (Fridman et al, 2011). According to the results from cytokine determinations of TDI-challenged ear skin, topical application of JAK inhibitors markedly inhibited the production of proinflammatory Th2 cytokines, including IL-1b, IL-4, IL-6, and TARC.…”

Epigallocatechin-3-gallate (EGCG) Suppresses the Trafficking of Lymphocytes to Epidermal Melanocytes <i>via</i> Inhibition of JAK2: Its Implication for Vitiligo Treatment

“…12) Due to their ability to selectively modulate immune function, targeted JAK inhibitors are attractive candidates for some skin diseases such as psoriasis and atopic dermatitis. [13][14][15] Our computer simulation result suggested that EGCG may bind to JAK2 protein (Fig. 1C).…”

Topical Therapies for Psoriasis

“…The JAK family is composed of four tyrosine kinases -JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) (Fridman et al, 2011). Members of the JAK family are essential for signaling by many cytokines and growth factors following their binding to specific receptors on the cell surface.…”