SummaryJanus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects. However, the high degree of structural conservation makes isoform-selective targeting a challenging task. Here, we present picomolar inhibitors with unprecedented kinome-wide selectivity for JAK3. Selectivity was achieved by concurrent covalent reversible targeting of a JAK3-specific cysteine residue and a ligand-induced binding pocket. We confirmed that in vitro activity and selectivity translate well into the cellular environment and suggest that our inhibitors are powerful tools to elucidate JAK3-specific functions.

For most inflammatory skin diseases topical glucocorticosteroids and traditional oral immunosuppressive drugs remain the principle treatment choices, but this has started to change. A deeper understanding in individual disease pathogenesis, basic immune mechanisms and molecular signalling pathways, together with advances in pharmaceutical drug development, allow us to interfere more precisely with disease-related factors. Some examples of inflammation-controlling interventions include antibodies neutralizing disease-associated cytokines, and small molecules targeting intracellular pathways relevant to cytokine production or cytokine signalling. So far, this is best established for psoriasis, an inflammatory skin disease dominated by Th17 cytokines. In this review, we focus on chronic inflammatory skin diseases where cytokines using type I/II cytokine receptors play a dominant role in disease pathogenesis and where novel treatments with inhibitors of the JAK/STAT pathway are already under clinical investigation. To better understand the rationale of using JAK/STAT inhibitors in the discussed skin diseases, we give an overview of important genetic and immunological associations with the JAK/STAT pathway and summarize the stage of clinical development of small molecular inhibitors. JAK/STAT inhibitors will presumably find wide application in dermatology, since they can be applied not only systematically but also topically for the treatment of inflammatory skin diseases.

T helper (Th) cells producing interleukin (IL)-17, IL-22, and tumor necrosis factor (TNF) form the key T cell population driving psoriasis pathogenesis. They orchestrate the inflammation in the skin that results in the proliferation of keratinocytes and endothelial cells. Besides Th17 cells, other immune cells that are capable of producing IL-17-associated cytokines participate in psoriatic inflammation. Recent advances in psoriasis research improved our understanding of the cellular and molecular players that are involved in Th17 pathology and inflammatory pathways in the skin. The inflammation-driving actions of TNF in psoriasis are already well known and antibodies against TNF are successful in the treatment of Th17-mediated psoriatic skin inflammation. A further key cytokine with potent IL-17-/IL-22-promoting properties is IL-23. Therapeutics directly neutralizing IL-23 or IL-17 itself are now extending the therapeutic spectrum of antipsoriatic agents and further developments are on the way. The enormous progress in psoriasis research allows us to control this Th17-mediated inflammatory skin disease in many patients.

Cutaneous lichen planus (CLP) and psoriasis (PSO) are both common chronic inflammatory skin diseases for which development of new treatments requires the identification of key targets. While PSO is a typical Th17/IL‐17‐disorder, there is some evidence that Th1/IFN‐ɣ dominate the inflammatory process in CLP. Nonetheless, the immunopathogenesis of CLP is not fully explained and key immunological factors still have to be recognized. In this study, we compared the immune signature of CLP lesions with the well‐characterized inflammation present in PSO skin. First, we analysed the histological and immunohistological characteristics of CLP and PSO. Second, we assessed the cytokine expression (IL1A, IL1B, IL4, IL6, IL8, IL10, IL17A, IL19, IL21, IL22, IL23A, IL13, IFNG, TNF, IL12A, IL12B and IL36G) of lesional skin of CLP with PSO by qPCR. Histology revealed a similar epidermal thickness in CLP and PSO. Immunohistochemically, both diseases presented with an inflammatory infiltrate mainly composed by CD3+CD4+ T cells rather than CD3+CD8+. Importantly, mRNA analysis showed a distinct cytokine signature: while levels of IL12B, IL1A, IL6 and IL23 were similar between the two groups, the characteristic PSO‐associated cytokines IL8, IL17A, IL22, IL19 and IL36G were expressed at very low levels in CLP. In contrast, CLP lesional skin was dominated by the expression of IFNG, IL21, IL4, IL12A and TNF. Immunohistochemistry confirmed the dominance of IL‐21, IFN‐ɣ and also pSTAT1 in the dermal infiltrate of CLP, while IL‐17A was more present in PSO. Collectively, this study improves our understanding of the immunological factors dominating CLP. The dominating cytokines and signalling proteins identified suggest that anti‐cytokine therapeutics like JAK inhibitors may be beneficial in CLP.

Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable colocalization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (23) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3. Herein, we describe detailed structure-activity relationships necessary for induction of the arginine pocket and the impact of this structural change on potency, isoform selectivity, and efficacy in cellular models. Furthermore, we evaluated the stability of this novel inhibitor class in in vitro metabolic assays and were able to demonstrate an adequate stability of key compound 23 for in vivo use.