title: 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.affiliation: Department of Drug Discovery, Incyte Corporation, Wilmington, Delaware 19880, USA. jfridman@incyte.com
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
authors.forename: Robert
authors.initials: R
authors.lastname: Collins
authors.forename: Timothy
authors.initials: T
authors.lastname: Burn
authors.forename: Claire L
authors.initials: CL
authors.lastname: Neilan
authors.forename: Denise
authors.initials: D
authors.lastname: Hertel
authors.forename: Nancy
authors.initials: N
authors.lastname: Contel
authors.forename: Patrick
authors.initials: P
authors.lastname: Haley
authors.forename: Beth
authors.initials: B
authors.lastname: Thomas
authors.forename: Jack
authors.initials: J
authors.lastname: Shi
authors.forename: Paul
authors.initials: P
authors.lastname: Collier
authors.forename: James D
authors.initials: JD
authors.lastname: Rodgers
authors.forename: Stacey
authors.initials: S
authors.lastname: Shepard
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
authors.forename: Gregory
authors.initials: G
authors.lastname: Hollis
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: Steven M
authors.initials: SM
authors.lastname: Friedman
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000078404:Epidermal Cells; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009570:Nitriles; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011565:Psoriasis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013552:Swine; D013556:Swine, Miniature; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D018925:Chemokines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C540383:ruxolitinib; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2