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Selective Janus kinase 1 inhibition resolves inflammation and restores hair growth offering a viable treatment option for alopecia areata

ABSTRACT: JAK inhibition by means of clinically available pan JAK inhibitors has recently demonstrated great efficacy in both restoring hair growth and resolving inflammation in the skin of patients with Alopecia Areata (AA). These effects are dose dependent and mainly efficacious at ranges close to a questionable risk profile. Given the great responses to JAK inhibition and the current lack of efficacious treatments in AA, it is exciting to explore the possibilities to separate the beneficial and adverse effects in order to provide a successful treatment option for these patients where the medical need is still vastly unmet. Selective JAK1 inhibition mainly affects genes downstream of STAT1, STAT3 & STAT6 in human immune cells. Importantly, pathways like T-cell differentiation and lymphopoiesis are less affected by the selective JAK1 inhibitor versus less specific JAK inhibitors like tofacitinib and ruxolitinib. These findings indicate that it is feasible to develop more selective and specific JAK1 inhibitors that are as efficacious as pan-JAK inhibitors but with a better safety profile as systemic exposure is mandatory for efficacy in this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94235 | GEO | 2023/01/30

REPOSITORIES: GEO

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Effect of systemic exposure of JAK1 Inhibition (AZ13748709) in C3H/HeJ Mice with Alopecia Areata In Vivo

Project description:JAK inhibition by means of clinically available pan JAK inhibitors has recently demonstrated great efficacy in both restoring hair growth and resolving inflammation in the skin of patients with Alopecia Areata (AA). These effects are dose dependent and mainly efficacious at ranges close to a questionable risk profile. Given the great responses to JAK inhibition and the current lack of efficacious treatments in AA, it is exciting to explore the possibilities to separate the beneficial and adverse effects in order to provide a successful treatment option for these patients where the medical need is still vastly unmet. We have demonstrated that specific inhibition of JAK1 at relevant concentrations produces a fast resolution of inflammation and complete restoration of hair growth in the C3H/HeJ model of AA and importantly, that systemic exposure is essential for efficacy.

2023-01-30 | GSE94236 | GEO

Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

Project description:Inhibition of Janus kinase (JAK) family enzymes has surged as a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, current available small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting their variable selectivity for JAK subtypes. Nonselective inhibition of multiple JAK enzymes is associated with increased side effects and has resulted in FDA-mandated black box warnings. Developing therapeutics to enable absolute JAK subtype selectivity is challenging and has not yet been achieved. Here, we harness RNA interference (RNAi) for rationally designing small interfering RNA (siRNA) therapeutics that offer sequence-specific gene silencing of JAK1, thus narrowing the spectrum of action on JAK-dependent cytokine signaling pathways to maintain efficacy and improve safety. We developed a fully chemically modified siRNA that supports efficient silencing of JAK1 expression in human skin explant and functional modulation of JAK1-dependent inflammatory signaling. A single injection of the JAK1 siRNA into mouse skin enables JAK1 silencing for 5 weeks in vivo. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work outlines a robust framework for designing targeted RNAi-based therapies and establishes a path toward novel siRNA treatments for inflammatory and autoimmune skin diseases.

2023-10-18 | GSE234070 | GEO

Expression profiling of primary leukemia initiating cell-enriched population induced by AML1-ETO9a

Project description:Combined gene expression and DNA occupancy profiling identifies JAK/STAT signaling as a valid therapeutic target of t(8;21) AML t(8;21) is commonly associated with acute myeloid leukemia (AML). The resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression and promoter occupancy profiling using a primary leukemia initiating cell-enriched population induced by AML1-ETO9a (AE9a). CD45, a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is greatly downregulated; furthermore JAK1 and JAK2 are upregulated in these leukemia cells. Consequently, JAK/STAT signaling is enhanced in the AE9a leukemia cells. Importantly, AE9a leukemia cells are highly susceptible to perturbation of JAK/STAT signaling, and a JAK2-selective inhibitor, TG101209, effectively targets these leukemia cells in vivo, suggesting the potential efficacy of JAK2 inhibitors in treating t(8;21) AML. Wild-type or AE9a leukemic samples in triplicate.

2012-09-04 | E-GEOD-15195 | biostudies-arrayexpress

RNA-seq of human leukemia cell lines, MHH-CALL-4 and MUTZ-5, treated either with Ruxolitinib, FX1, or their combination.

Project description:CRLF2-rearranged acute lymphoblastic leukemia (ALL) is associated with poor clinical outcomes. Although JAK1/2 is activated in this type of ALL, treatment with JAK1/2 inhibitors is insufficient in inhibiting cell growth and inducing apoptosis. BCL6 upregulation upon JAK inhibition may account for this insufficiency. Therefore, we compared gene expression changes of two CRLF2-rearranged ALL cell lines, MHH-CALL-4 and MUTZ-5, treated with either ruxolitinib(a JAK1/2 inhibitor), FX1(a BCL6 inhibitor), their combination, or control.

2022-07-31 | E-MTAB-10755 | biostudies-arrayexpress

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

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

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

Comparative study of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in MCL

Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound. Global RNA expression in primary cells from two MCL patients treated with a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor for 8 hours

2013-12-14 | E-GEOD-53309 | biostudies-arrayexpress

Expression profiling of primary leukemia initiating cell-enriched population induced by AML1-ETO9a

2012-09-04 | GSE15195 | GEO

Metabolic profiling of rheumatoid arthritis neutrophils reveals altered energy metabolism that is not affected by JAK inhibition

Project description:Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function is directly affected by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically effective treatments for RA. However clinical trials have reported increased infection rates and transient neutropenia during therapy. The subtle differences in the mode of action, efficacy and safety of JAK inhibitors has been the primary research topic of many clinical trials and systematic reviews, to provide a more precise and targeted treatment to patients. The aim of this study was to determine both the differences in the metabolome of neutrophils from healthy controls and people with RA, and the effect of different JAK inhibitors on the metabolome of healthy and RA neutrophils. Isolated neutrophils from healthy controls (HC) (n=6) and people with RA (n=7) were incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200ng/mL) for 2h. Metabolites were extracted and 1H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models show a divergent metabolic pattern in RA neutrophils compared to HC at baseline (F1 score = 86.7%) driven by energy metabolites (ATP, ADP, GTP and glucose). No difference was observed in the neutrophil metabolome when treated with JAK inhibitors. However, JAK inhibitors significantly inhibited ROS production and baricitinib decreased NET production (p-value<0.05). Bacterial killing was not inhibited by JAK inhibitors, indicating their effect on neutrophils is beneficial to inhibit joint damage in RA without impairing host defence. This study highlights altered energy metabolism in RA neutrophils which may explain the cause of their dysregulation in inflammatory disease.

2023-07-11 | MTBLS4766 | MetaboLights

JAK dependent survival of ALK- ALCL

Project description:Activating JAK and STAT mutations were discovered in many T-cell malignancies including ALK- anaplastic large cell lymphomas (ALCL). However, such mutations often occur in a minority of patients. To investigate the clinical application of targeting Janus Kinase (JAK) for ALK- ALCL, we treated ALK- cell lines of different histologic origins with JAK inhibitors. Interestingly, most exogenous cytokine independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with STAT3 phosphorylation status of tumor cells. Employing retroviral shRNA knockdown, we demonstrated that these JAK inhibitor sensitive cells were dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some but not all JAK inhibitor sensitive cells. Moreover, the mutations alone could not explain the JAK1/STAT3 dependency as wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in select JAK inhibitor sensitive cells. High levels of cytokine expression including IL-6 were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest cytokine receptor signaling was required for tumor cell survival in diverse forms of ALK- ALCL even in the presence of JAK1/STAT3 mutations. Therefore, JAK-inhibitor therapy might benefit patients with ALK- ALCL that are pSTAT3+.

2017-08-22 | GSE96048 | GEO

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