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Selective inhibition of JAK1 with filgotinib reverses pathogenic processes in the DSS preclinical model for IBD

ABSTRACT: The pathogenesis of inflammatory bowel diseases (IBD) is associated with a dysregulated mucosal immune response. The signaling of several cytokines regulating this immune response is mediated by kinases of the JAK family, i.e. JAK1, JAK2, JAK3 and TYK2. Filgotinib is a JAK1-selective inhibitor with demonstrated efficacy in phase 2 trials in patients with rheumatoid arthritis (RA) and Crohn’s disease (CD). Here, we investigated the effects of filgotinib on the DSS (dextran sulfate sodium) mouse model

ORGANISM(S): Mus musculus

PROVIDER: GSE105417 | GEO | 2020/10/19

REPOSITORIES: GEO

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Selective inhibitors of JAK1 targeting a subtype-restricted allosteric cysteine

Project description:The JAK family of non-receptor tyrosine kinases includes four subtypes (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immuno(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor subtype selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here, we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent transphosphorylation and cytokine signaling, while appearing to act largely as “silent” ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented subtype selectivity.

2023-07-20 | PXD031384 | Pride

Effect of JAK1/3 blockade on IL2 response in NK cells

Project description:IL2 signals are transmitted through JAK1 and JAK3, but the transcriptomic consequences of each to the overall response is unclear. Here we analyzed the relative contribution of JAK1 and JAK3 to the NK cell IL2 response in vitro using titrated doses of isoform specific JAK inhibitors. Blockade of JAK1 and JAK3 have unequal effects on IL2-induced transcripts at pharmacologically relevant doses. Splenic NK cells were isolated by negative selection from 6wk old male C57BL/6 mice. These were cultured with IL2 (250U/ml) in the presence or absence of JAK1/3 inhibitors for 8hrs in vitro. Cells were then transferred directly into TriZol. RNA was prepared in Trizol for gene expression profiling by Affymetrix Mouse Gene 1.0 ST Arrays.

2016-07-20 | E-GEOD-84562 | biostudies-arrayexpress

Effect of JAK1/3 blockade on IL2 response in NK cells

2016-07-20 | GSE84562 | GEO

JAK3/TEC and TYK2/JAK1 inhibitors demonstrate significant improvement in scalp alopecia areata biomarkers

Project description:We present the biopsy sub-study results from the first randomized, placebo-controlled clinical trial in patients with alopecia areata (AA) with ≥50% scalp hair loss and ≤7 years since the last AA episode. In this sub-study, we evaluated the molecular responses to PF-06651600, an oral inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, and PF-06700841, an oral TYK2/JAK1 inhibitor, versus placebo in nonlesional and lesional scalp biopsies of biopsy samples from patients with AA.

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JAK3/TEC and TYK2/JAK1 inhibitors demonstrate significant improvement in scalp alopecia areata biomarkers

Project description:JAK3/TEC and TYK2/JAK1 inhibitors demonstrate significant improvement in scalp alopecia areata biomarkers

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Selective inhibition of JAK1 with filgotinib reverses pathogenic processes in the DSS preclinical model for IBD

Project description:Selective inhibition of JAK1 with filgotinib reverses pathogenic processes in the DSS preclinical model for IBD

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RNA-seq analysis of Jak1 KO and wt LT-HSCs

Project description:Previous studies have illustrated the importance of Jak1-mediated cytokine signaling in immunological and neoplastic diseases such that JAK1 inhibition is currently being investigated in clinical trials. However, the role of Jak1 in hematopoietic stem cell (HSC) function has not been delineated. Here we show that conditional Jak1 loss in hematopoietic cells reduces HSCs and markedly alters lymphoid/myeloid differentiation in vivo. Jak1-deficient stem cells exhibit decreased competitiveness in vivo, and are unable to rescue hematopoiesis in the setting of myelosuppression. Jak1-deficient HSCs show increased quiescence, an inability to enter the cell cycle in response to hematopoietic stress, and do not respond to type I interferons demonstrating Jak1 as a central node for interferon signaling in HSCs. Moreover, the HSC defect induced by Jak1 loss is not fully rescued by expression of a constitutively active Jak2 allele. Our data highlights an essential role for Jak1 in HSC homeostasis and stress response.

2017-12-31 | GSE85745 | GEO

Gene expression profiling upon knockdown of JAK1 in IM9 cells

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2012-06-27 | E-GEOD-37012 | biostudies-arrayexpress

Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor, PF 06700841, Reveal Reduction of Skin Inflammation in Plaque Psoriasis

Project description:The interleukin (IL)-23/T-helper type 17 cell axis is a target for psoriasis. The tyrosine kinase 2 (TYK2)/Janus kinase 1 (JAK1) inhibitor, PF 06700841, will directly suppress TYK2-dependent IL-12 and IL-23 signaling and JAK1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF 06700841 improves the clinical manifestations of psoriasis. Patients (n=30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n=14) or 100 mg (n=7) PF 06700841, or placebo (n=9) for 28 days. Biopsies were taken from non-lesional and lesional skin at baseline, weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and RT-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and ~70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF 06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of pro-inflammatory cytokines that require TYK2 and JAK1 for signal transduction.

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Project description:General impact of Jak1 and Jak2 inhibition on IFNg-mediated target gene expression. U4C-Jak1AS and g2A-Jak2AS cells were stimulated with IFNg and treated with either 1NM-PP1 (to inhibit the activity only of the analog-sensitive mutant) or JI1 (to suppress both wild-type and analog-sensitive Jaks) for 24h.

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