Selective inhibition of JAK1 with filgotinib reverses pathogenic processes in the DSS preclinical model for IBD
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ABSTRACT:
PROVIDER: PRJNA415138 | ENA |
REPOSITORIES: ENA
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Project description: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
2020-10-19 | GSE105417 | GEO
Project description:Atopic dermatitis (AD), a chronic, pruritic skin disease, affects 10%-30% of children and up to 14% of adults in developed countries. Since current AD treatments may lead to systemic drug exposure and AD pathophysiology is partially mediated by JAK1/3 signaling, ATI-1777, a potent and selective JAK1/3 inhibitor, was designed with multiple sites of metabolism to deliver local efficacy in the skin and limit systemic exposure. In preclinical studies, ATI-1777 selectively inhibited JAK1/3 with limited systemic exposure and without any adverse effects. ATI-1777-AD-201 (NCT04598269), a Phase 2a, first-in-human, randomized, double-blind,vehicle-controlled, parallel-group study, evaluated the efficacy, safety, tolerability, and pharmacokinetics of ATI-1777 topical solution in 48participants with AD over 4 weeks. The primary outcome was reduction of a modified EASI score from baseline; reduction was significantly greater in the ATI-1777 group at Day28 compared to vehicle (percent reduction from baseline 74.45% [SE6.455] and 41.43% [SE6.189], respectively [p<0.001]). Average plasma concentrations of ATI-1777 were <5% of the IC50 of ATI-1777 for inhibiting JAK1/3. No deaths or serious adverse events were reported. This demonstrates that topical ATI-1777 does not lead to pharmacologically relevant systemic drug exposure and may reduce clinical signs of AD.
2023-11-20 | GSE244201 | GEO
Project description:Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. Somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis; We used microarray to compare the gene expression profile of JAK1 mutation positive or negative ALL blasts Experiment Overall Design: Thawed or freshly isolated T-ALL cells (>90% blasts) were homogenized, total RNA was extracted and hybridized on Affymetrix microarrays
2009-10-02 | E-GEOD-18239 | biostudies-arrayexpress
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
Project description:Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. Somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis We used microarray to compare the gene expression profile of JAK1 mutation positive or negative ALL blasts
2009-09-24 | GSE18239 | GEO
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
Project description:Mucosal-luminal interface (MLI) samples were collected from a cohort of children with new-onset IBD and microbial cells were harvested and processed for metaproteomic analysis. Deep metaproteomics data analysis was then performed for better understanding the MLI microbiota functions in the development of pediatric IBD.
2018-08-03 | PXD007819 | Pride
Project description:Natural Killer (NK) cells are primary effectors of innate immunity directed against transformed cells. In response, tumor cells have developed mechanisms to evade NK cell-mediated lysis but the molecular basis for target cell resistance is not well understood. In the present study, we used a lentiviral shRNA library targeting more than 1000 human genes to identify 83 genes that promote target cell resistance to human NK cells. Many of the genes identified in this genetic screen belong to common signaling pathways, however, none of these genes have previously been known to modulate susceptibility of human tumor cells to immunologic destruction. In particular, gene silencing of two members of the JAK family (JAK1 and JAK2) in a variety of tumor cell targets increased their susceptibility to NK-mediated lysis and induced increased secretion of interferon gamma (IFN-gamma by NK cells. Treatment of tumor cells with JAK inhibitors also induced increased susceptibility to NK cell activity. These findings may have important clinical implications and suggest that small molecule inhibitors of tyrosine kinases being developed as therapeutic anti-tumor agents may also have significant immunologic effects in vivo. IM9 cells were transduced with shRNA-encoding vectors and selected with Puromycin. Two vectors were specifically targeting JAK1 (JAK1-1 and JAK1-3) and one vector encoded an irrelevant control shRNA (CTRL-2). Total RNA was obtained from the parental IM9 cell line, the control-shRNA expressing IM9 cells, the JAK1-1-shRNA and JAK1-3-shRNA expressing IM9 cells in 2 separate experiments (Exp1 and Exp2).
2012-06-27 | E-GEOD-37012 | biostudies-arrayexpress
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
Project description:Combining metabolomics analyses with an IFN-stimulated response elements reporter system, we identify spermine as a cellular metabolite brake for JAK1 signaling. Spermine directly binds to FERM and SH2 domains of JAK1 to impair IFNAR2-JAK1 interaction. Spermine suppresses JAK1 phosphorylation triggered by types I and II cytokines, including IFN-I/II, IL-2, and IL-6. Spermine treatment attenuates autoimmune pathogenesis in a SLE murine model and reduces IFN-I signaling in monocytes from SLE patients, which have reduced spermine levels.
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