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.

• Authors: Jordan S Fridman, Peggy A Scherle, Robert Collins, Timothy Burn, Claire L Neilan, Denise Hertel, Nancy Contel, Patrick Haley, Beth Thomas, Jack Shi, Paul Collier, James D Rodgers, Stacey Shepard, Brian Metcalf, Gregory Hollis, Robert C Newton, Swamy Yeleswaram, Steven M Friedman, Kris Vaddi
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 131 Issue 9 Pg. 1838-44 (Sep 2011) ISSN: 1523-1747 [Electronic] United States
• PMID: 21677670 (Publication Type: Journal Article)

Chemical References

• Chemokines
• Nitriles
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• STAT3 Transcription Factor
• STAT3 protein, human
• ruxolitinib
• JAK1 protein, human
• JAK2 protein, human
• Janus Kinase 1
• Janus Kinase 2

Topics

• Animals
• Cells, Cultured
• Chemokines (metabolism)
• Dermatitis, Atopic (drug therapy, metabolism, pathology)
• Epidermal Cells
• Humans
• Hypersensitivity, Delayed (drug therapy, metabolism, pathology)
• Janus Kinase 1 (antagonists & inhibitors, metabolism)
• Janus Kinase 2 (antagonists & inhibitors, metabolism)
• Keratinocytes (cytology, drug effects, metabolism)
• Mice
• Nitriles
• Phosphorylation (drug effects, physiology)
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Psoriasis (drug therapy, metabolism, pathology)
• Pyrazoles (chemistry, pharmacology)
• Pyrimidines
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects, physiology)
• Swine
• Swine, Miniature
• T-Lymphocytes (cytology, drug effects, metabolism)