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Drug Design, Development and Therapy 2022Interstitial lung disease (ILD) refers to a heterogeneous group of diseases characterized by lung fibroblast proliferation, interstitial inflammation, and... (Review)
Review
Interstitial lung disease (ILD) refers to a heterogeneous group of diseases characterized by lung fibroblast proliferation, interstitial inflammation, and fibrosis-induced lung damage. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is known to be activated by pro-fibrotic/pro-inflammatory cytokines such as IL-6 and IL-13, whose levels are elevated in ILD. The overexpression of growth factors such as transforming growth factor β1 in ILD activates the JAK/STAT pathway through classical or non-classical pathways, promotes macrophage activation, increases the release of pro-inflammatory and pro-fibrosis factors, and facilitates fibroblast differentiation into myofibroblasts. These findings implicate that the JAK/STAT pathway plays an important role in the course of ILD. Recent evidence also suggests that JAK inhibition alleviates excessive inflammation and pulmonary fibrosis. Accordingly, the JAK inhibitors may serve as promising drugs for the treatment of JAK/STAT-induced ILD.
Topics: Fibrosis; Humans; Inflammation; Janus Kinase 1; Janus Kinase 2; Janus Kinase Inhibitors; Janus Kinases; Lung Diseases, Interstitial; Pulmonary Fibrosis; STAT Transcription Factors; Signal Transduction
PubMed: 35400994
DOI: 10.2147/DDDT.S353494 -
The Korean Journal of Internal Medicine Mar 2016Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However,... (Review)
Review
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaïve, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD.
Topics: Administration, Oral; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Disability Evaluation; Drug Administration Schedule; Humans; Janus Kinases; Molecular Targeted Therapy; Predictive Value of Tests; Protein Kinase Inhibitors; Recovery of Function; Remission Induction; Signal Transduction; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 26932398
DOI: 10.3904/kjim.2015.137 -
Journal of Thrombosis and Haemostasis :... May 2023Vascular activation is characterized by increased proinflammatory, pro thrombotic, and proadhesive signaling. Several chronic and acute conditions, including...
BACKGROUND
Vascular activation is characterized by increased proinflammatory, pro thrombotic, and proadhesive signaling. Several chronic and acute conditions, including Bcr-abl-negative myeloproliferative neoplasms (MPNs), graft-vs-host disease, and COVID-19 have been noted to have increased activation of the janus kinase (JAK)-signal transducer and downstream activator of transcription (STAT) pathways. Two notable inhibitors of the JAK-STAT pathway are ruxolitinib (JAK1/2 inhibitor) and fedratinib (JAK2 inhibitor), which are currently used to treat MPN patients. However, in some conditions, it has been noted that JAK inhibitors can increase the risk of thromboembolic complications.
OBJECTIVES
We sought to define the anti-inflammatory and antithrombotic effects of JAK-STAT inhibitors in vascular endothelial cells.
METHODS
We assessed endothelial activation in the presence or absence of ruxolitinib or fedratinib by using immunoblots, immunofluorescence, qRT-PCR, and function coagulation assays. Finally, we used endothelialized microfluidics perfused with blood from normal and JAK2 individuals to evaluate whether ruxolitinib and fedratinib changed cell adhesion.
RESULTS
We found that both ruxolitinib and fedratinib reduced endothelial cell phospho-STAT1 and STAT3 signaling and attenuated nuclear phospho-NK-κB and phospho-c-Jun localization. JAK-STAT inhibition also limited secretion of proadhesive and procoagulant P-selectin and von Willebrand factor and proinflammatory IL-6. Likewise, we found that JAK-STAT inhibition reduced endothelial tissue factor and urokinase plasminogen activator expression and activity.
CONCLUSIONS
By using endothelialized microfluidics perfused with whole blood samples, we demonstrated that endothelial treatment with JAK-STAT inhibitors prevented rolling of both healthy control and JAK2 MPN leukocytes. Together, these findings demonstrate that JAK-STAT inhibitors reduce the upregulation of critical prothrombotic pathways and prevent increased leukocyte-endothelial adhesion.
Topics: Humans; Janus Kinases; Signal Transduction; Endothelial Cells; STAT Transcription Factors; COVID-19; Janus Kinase 2; Leukocytes
PubMed: 36738826
DOI: 10.1016/j.jtha.2023.01.027 -
Journal of Crohn's & Colitis Jul 2017Inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are disabling conditions characterised by chronic, relapsing inflammation of the... (Review)
Review
Inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are disabling conditions characterised by chronic, relapsing inflammation of the gastrointestinal tract. Current treatments are not universally effective or, in the case of therapeutic antibodies, are hampered by immune responses. Janus kinase inhibitors are orally delivered small molecules that target cytokine signalling by preventing phosphorylation of Janus kinases associated with the cytokine receptor. Subsequently, phosphorylation of signal transducers and activators of transcription that relay Janus kinase signalling and transcription of cytokines in the nucleus will be diminished. Key cytokines in the pathogenesis of inflammatory bowel diseases are targeted by Janus kinase inhibitors. Several Janus kinase inhibitors are in development for the treatment of inflammatory bowel diseases. Tofacitinib, inhibiting signalling via all Janus kinase family members, was effective in phase 2 and 3 trials in moderate-severe ulcerative colitis. GSK2586184, a Janus kinase 1 selective inhibitor, induced clinical and endoscopic response in ulcerative colitis; however, the study was discontinued at an early stage due to liver toxicity observed in systemic lupus patients receiving the drug. Filgotinib, a Janus kinase 1 selective inhibitor investigated in treatment of Crohn's disease, was superior to placebo. As adverse events associated with the broad immunological effect of these agents have been reported, the future application of these drugs is potentially limited. We will discuss the treatment efficacy of Janus kinase inhibition in inflammatory bowel diseases, how current Janus kinase inhibitors available target immune responses relevant in inflammatory bowel disease, and whether more specific kinase inhibition could be effective.
Topics: Animals; Cytokines; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Mutation; Piperidines; Pyrimidines; Pyrroles; STAT Transcription Factors; Signal Transduction
PubMed: 28158411
DOI: 10.1093/ecco-jcc/jjx003 -
Genes May 2021Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with... (Review)
Review
Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with Philadelphia-positive ALL although lacking the pathognomonic BCR-ABL1 oncoprotein. Its prevalence increases with age and similar to -positive ALL, Ph-like ALL is characterized by or other B-lymphoid transcription factor gene deletions and by poor outcome to conventional therapeutic approaches. Genetic alterations are highly heterogenous across patients and include gene fusions, sequence mutations, DNA copy number changes and cryptic rearrangements. These lesions drive constitutively active cytokine receptor and kinase signaling pathways which deregulate ABL1 or JAK signaling and more rarely other kinase-driven pathways. The presence of activated kinase alterations and cytokine receptors has led to the incorporation of targeted therapy to the chemotherapy backbone which has improved treatment outcome for this high-risk subtype. More recently, retrospective studies have shown the efficacy of immunotherapies including both antibody drug-conjugates and chimeric antigen receptor T cell therapy and as they are not dependent on a specific genetic alteration, it is likely their use will increase in prospective clinical trials. This review summarizes the genomic landscape, clinical features, diagnostic assays, and novel therapeutic approaches for patients with Ph-like ALL.
Topics: Genetic Heterogeneity; Humans; Immunotherapy; Janus Kinases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl
PubMed: 34062932
DOI: 10.3390/genes12050687 -
Gut and Liver Jan 2015Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different... (Review)
Review
Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are be-ing investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are be-ing used for treating ulcerative colitis. Recently, golimumab, another anti-TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage.
Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Factors; Cell Adhesion Molecules; Colitis, Ulcerative; Humans; Infliximab; Janus Kinases; Piperidines; Pyrimidines; Pyrroles
PubMed: 25547087
DOI: 10.5009/gnl14226 -
International Journal of Molecular... Oct 2021For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant... (Review)
Review
For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn's disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.
Topics: Adamantane; Colitis; Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Niacinamide; Piperidines; Pyridines; Pyrimidines; Pyrroles; Triazoles
PubMed: 34768752
DOI: 10.3390/ijms222111322 -
Pharmacological Research Jun 2024The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines,... (Review)
Review
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation.
Topics: Humans; Janus Kinases; STAT Transcription Factors; Drug Discovery; Animals; Signal Transduction; Janus Kinase Inhibitors; Molecular Targeted Therapy
PubMed: 38777110
DOI: 10.1016/j.phrs.2024.107217 -
BioDrugs : Clinical Immunotherapeutics,... Feb 2019Cytokines, many of which signal through the JAK-STAT (Janus kinase-Signal Transducers and Activators of Transcription) pathway, play a central role in the pathogenesis... (Review)
Review
Cytokines, many of which signal through the JAK-STAT (Janus kinase-Signal Transducers and Activators of Transcription) pathway, play a central role in the pathogenesis of inflammatory and autoimmune diseases. Currently three JAK inhibitors have been approved for clinical use in USA and/or Europe: tofacitinib for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, baricitinib for rheumatoid arthritis, and ruxolitinib for myeloproliferative neoplasms. The clinical JAK inhibitors target multiple JAKs at high potency and current research has focused on more selective JAK inhibitors, almost a dozen of which currently are being evaluated in clinical trials. In this narrative review, we summarize the status of the pan-JAK and selective JAK inhibitors approved or in clinical trials, and discuss the rationale for selective targeting of JAKs in inflammatory and autoimmune diseases.
Topics: Animals; Arthritis, Rheumatoid; Autoimmune Diseases; Cytokines; Humans; Janus Kinases; Protein Kinase Inhibitors
PubMed: 30701418
DOI: 10.1007/s40259-019-00333-w -
Clinical and Experimental Immunology Apr 2014Protein kinases mediate protein phosphorylation, which is a fundamental component of cell signalling, with crucial roles in most signal transduction cascades: from... (Review)
Review
Protein kinases mediate protein phosphorylation, which is a fundamental component of cell signalling, with crucial roles in most signal transduction cascades: from controlling cell growth and proliferation to the initiation and regulation of immunological responses. Aberrant kinase activity is implicated in an increasing number of diseases, with more than 400 human diseases now linked either directly or indirectly to protein kinases. Protein kinases are therefore regarded as highly important drug targets, and are the subject of intensive research activity. The success of small molecule kinase inhibitors in the treatment of cancer, coupled with a greater understanding of inflammatory signalling cascades, has led to kinase inhibitors taking centre stage in the pursuit for new anti-inflammatory agents for the treatment of immune-mediated diseases. Herein we discuss the main classes of kinase inhibitors; namely Janus kinase (JAK), mitogen-activated protein kinase (MAPK) and spleen tyrosine kinase (Syk) inhibitors. We provide a mechanistic insight into how these inhibitors interfere with kinase signalling pathways and discuss the clinical successes and failures in the implementation of kinase-directed therapeutics in the context of inflammatory and autoimmune disorders.
Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Humans; Intracellular Signaling Peptides and Proteins; Janus Kinases; Models, Biological; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Signal Transduction; Syk Kinase; p38 Mitogen-Activated Protein Kinases
PubMed: 24313320
DOI: 10.1111/cei.12248