1078 Topical administration of MDI1228, a novel pan-JAK inhibitor, effectively suppresses the development of skin inflammation in mice

The JAK-STAT pathway mediates signal transduction evens downstream of several cytokine receptors, which are involved in the pathological processes allergic, autoimmune and inflammatory diseases, therefore JAK inhibition is a promising therapeutic strategy for skin diseases. Here we developed novel small molecule pan-JAK inhibitor, MDI1228, investigated its vivo effect on development inflammation 3 distinct mouse dermatitis models, as well vitro anti-inflammatory against cytokine-mediated activation primary lymphocytes dermal fibroblasts (dFBs). We found that topical application MDI1228 was effective suppressing epidermal hyperplasia, erythema cell infiltration all three models. In MC903-induced AD model, inhibited STAT6 phosphorylation expression IL4, IL13 POSTN. hapten-induced ACD suppressed IFNγ genes IFNGR pathways. imiquimod-induced psoriasis IL17a genes. Furthermore, differentiation/polarization naïve T cells under either Th1, Th2 or Th17 polarizing conditions, attenuated responses human dFBs. Additionally, 10-fold more than tofacitinib, FDA-approved inhibiting IFNβ-mediated STAT1 TYK2 Taken together, have shown has broad spectrum inhibitory immune system mediated by key cytokines including IFNβ, IFNγ, IL4 and/or IL17A, result it effectively suppresses both allergic inflammation. These results indicate candidate drug various types dermatitis.