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Drugs Aug 2020Janus kinase (JAK) is a signal transducer and activator of a protein transcription system that transduces signals from cell surface cytokine and growth factor receptors... (Review)
Review
Janus kinase (JAK) is a signal transducer and activator of a protein transcription system that transduces signals from cell surface cytokine and growth factor receptors to the nucleus. Recently developed JAK inhibitors (JAKinibs) inhibit JAKs non-selectively or selectively and down-regulate the effects of corresponding ligands (i.e. cytokines and growth factors). JAKinibs are efficacious against rheumatoid arthritis and other immune-mediated inflammatory diseases and are being increasingly prescribed clinically. Regarding safety, JAKinib use is associated with common or unique changes in laboratory parameters; however, incidence rates of serious adverse drug reactions (ADRs) associated with these changes are low. Opportunistic and other infections, including tuberculosis, are the most critical ADRs of treatment with JAKinibs, and screening and monitoring of patients should be carefully performed. Incidence rates of herpes zoster (HZ) in patients receiving JAKinibs are high in Japan and Korea, and modestly high in other countries. Filgotinib may not be associated with an elevated risk for HZ, but long-term safety data are lacking. Data from clinical development programmes and post-marketing surveillance have indicated no increased risk for malignancy or serious cardiac events; however, long-term observational studies are necessary. Despite the non-elevated risk of gastrointestinal perforations, patients with older age and/or a history of diverticulitis or receiving non-steroidal anti-inflammatory drugs should be carefully evaluated to determine the risk-benefit balance. The incidence rates of venous thromboembolism with all approved doses are similar to that expected in the population, although there are discrepancies in the placebo-controlled portion of the baricitinib clinical development programmes. Regulatory agencies in the USA and Europe suggested a higher risk for thrombotic events in patients receiving JAKinibs. Pharmacokinetic studies demonstrated that dose adjustment should be considered for JAKinib use in patients with moderate-to-severe renal or hepatic dysfunction, depending on the metabolism of each drug. Long-term observational studies enrolling patients with diverse clinical backgrounds are required to strike a risk-benefit balance in clinical settings.
Topics: Arthritis, Rheumatoid; Azetidines; Humans; Inflammation; Janus Kinase Inhibitors; Janus Kinases; Purines; Pyrazoles; Sulfonamides
PubMed: 32681420
DOI: 10.1007/s40265-020-01349-1 -
Journal of Cellular and Molecular... Apr 2022A subset of cytokines triggers the JAK-STAT pathway to exert various functions such as the induction of inflammation and immune responses. The receptors for these... (Review)
Review
A subset of cytokines triggers the JAK-STAT pathway to exert various functions such as the induction of inflammation and immune responses. The receptors for these cytokines are dimers/trimers of transmembrane proteins devoid of intracellular kinase activity. Instead, they rely on Janus kinases (JAKs) for signal transduction. Classical JAK-STAT signalling involves phosphorylation of cytokine receptors' intracellular tyrosines, which subsequently serve as docking sites for the recruitment and activation of STATs. However, there is evidence to show that several cytokine receptors also use a noncanonical, receptor tyrosine-independent path to induce activation of STAT proteins. We identified two main alternative modes of STAT activation. The first involves an association between a tyrosine-free region of the cytokine receptor and STATs, while the second seems to depend on a direct interaction between JAK and STAT proteins. We were able to identify the use of noncanonical mechanisms by almost a dozen cytokine receptors, suggesting they have some importance. These alternative pathways and the receptors that employ them are discussed in this review.
Topics: Janus Kinases; Phosphorylation; Receptors, Cytokine; STAT Transcription Factors; Signal Transduction
PubMed: 35238133
DOI: 10.1111/jcmm.17168 -
Best Practice & Research. Clinical... Sep 2017Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently identified high risk disease subtype characterized by a gene expression profile... (Review)
Review
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently identified high risk disease subtype characterized by a gene expression profile similar to that observed in Philadelphia chromosome-positive (Ph-positive) ALL, but without an underlying BCR-ABL1 translocation. Adults and children with Ph-like ALL harbor a diversity of alterations that all lead to activated kinase signaling. Outcomes for patients with Ph-like ALL are poor, which has prompted investigation into the role of tyrosine kinase inhibitor (TKI)-based therapies for this disease. Several clinical trials are now ongoing that include screening for the Ph-like signature and treatment of patients with Ph-like ALL with TKI therapy. This review examines how testing for Ph-like ALL is being incorporated into clinical trials.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Dasatinib; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cell Transplantation; Humans; Imatinib Mesylate; Janus Kinases; Molecular Targeted Therapy; Nitriles; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; STAT Transcription Factors; Signal Transduction; Survival Analysis; Transplantation, Homologous
PubMed: 29050695
DOI: 10.1016/j.beha.2017.06.001 -
Skin Therapy Letter May 2018The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription... (Review)
Review
The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia. Both first and second generation Janus kinase inhibitors have become promising treatment modalities for dermatologic conditions such as psoriasis, atopic dermatitis, alopecia areata, vilitigo, dermatomyositis, and graft-versus-host disease. Future promising areas of investigation include treatment of cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.
Topics: Anti-Inflammatory Agents; Dermatologic Agents; Dermatology; Humans; Janus Kinase Inhibitors; Janus Kinases; Skin Diseases
PubMed: 29772037
DOI: No ID Found -
Expert Review of Hematology Aug 2015Polycythemia vera (PV) is a hematopoietic proliferative disorder associated with Janus-associated kinase/signal transducer and activator of transcription pathway... (Review)
Review
Polycythemia vera (PV) is a hematopoietic proliferative disorder associated with Janus-associated kinase/signal transducer and activator of transcription pathway dysregulation resulting in erythrocytosis and, possibly, leukocytosis and thrombocytosis. Patients diagnosed with PV experience a broad range of symptoms associated with a reduced quality of life, often develop splenomegaly, and have an increased risk of death compared with age-matched subjects without PV. Current treatment options, notably hydroxyurea, help with disease management; however, insufficient efficacy or progressive resistance occurs in some patients, highlighting the need for new treatment options. Ruxolitinib is an oral JAK1/JAK2 inhibitor that has been evaluated in Phase II and III clinical trials in patients with PV, who are intolerant of or resistant to hydroxyurea. In this setting, ruxolitinib treatment has demonstrated normalization of blood cell counts, reduction in splenomegaly and improvements in PV-related symptom burden.
Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Janus Kinases; Nitriles; Polycythemia Vera; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome
PubMed: 25980454
DOI: 10.1586/17474086.2015.1045869 -
Scandinavian Journal of Immunology Jun 2014The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway controls multiple biological processes in metazoan development and tissue... (Review)
Review
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway controls multiple biological processes in metazoan development and tissue homoeostasis. This creates a need for tight regulatory mechanisms to ensure proper responses. The core components of the pathway, as well as many of the regulatory molecules, are conserved in evolution and thus share similarities in organisms such as humans and fruit flies. Therefore, the fruit fly provides an amenable model system for elucidating the in vivo roles of the JAK/STAT pathway and its regulators, which are challenging to demonstrate in mammalian systems. This review will focus on describing recent advances in understanding the importance of JAK/STAT signalling in Drosophila immunity.
Topics: Animals; Drosophila melanogaster; Hematopoiesis; Immunity, Cellular; Intestines; Janus Kinases; STAT Transcription Factors; Signal Transduction; Virus Diseases
PubMed: 24673174
DOI: 10.1111/sji.12170 -
International Journal of Molecular... Mar 2023The Janus kinases (JAKs) are a family of non-receptor cytosolic protein kinases critical for immune signaling. Many covalently bound ligands of JAK3 inhibitors have been...
The Janus kinases (JAKs) are a family of non-receptor cytosolic protein kinases critical for immune signaling. Many covalently bound ligands of JAK3 inhibitors have been reported. To help design selective JAK inhibitors, in this paper, we used five model proteins to study the subtype selectivity of and the mutational effects on inhibitor binding. We also compared the Covalent Dock programs from the Schrodinger software suite and the MOE software suite to determine which method to use for the drug design of covalent inhibitors. Our results showed that the docking affinity from 4Z16 (JAK3 wild-type model), 4E4N (JAK1), 4D1S (JAK2), and 7UYT (TYK2) from the Schrödinger software suite agreed well with the experimentally derived binding free energies with small predicted mean errors. However, the data from the mutant 5TTV model using the Schrödinger software suite yielded relatively large mean errors, whereas the MOE Covalent Dock program gave small mean errors in both the wild-type and mutant models for our model proteins. The docking data revealed that Leu905 of JAK3 and the hydrophobic residue at the same position in different subtypes (Leu959 of JAK1, Leu932 of JAK2, and Val981 of TYK2) is important for ligand binding to the JAK proteins. Arg911 and Asp912 of JAK3, Asp939 of JAK2, and Asp988 of TYK2 can be used for selective binding over JAK1, which contains Lys965 and Glu966 at the respective positions. Asp1021, Asp1039, and Asp1042 can be utilized for JAK1-selective ligand design, whereas Arg901 and Val981 may help guide TYK2-selective molecule design.
Topics: Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Janus Kinases; Ligands; Protein Kinase Inhibitors; Signal Transduction
PubMed: 37047004
DOI: 10.3390/ijms24076023 -
Journal of Asian Natural Products... 2014Janus kinase/signal transducer and activator of transcriptions (JAK/STAT) signaling pathway is one of the major signaling pathways involved in a variety of human... (Review)
Review
Janus kinase/signal transducer and activator of transcriptions (JAK/STAT) signaling pathway is one of the major signaling pathways involved in a variety of human physiological and pathological process. The proteins of JAK/STAT pathway or interferon response element (such as JAK, STAT, Src, SOCS, 2'5'-OAS, and ISRE) might be as drug targets for the study of physiological processes and treatment of related diseases, including cell proliferation, differentiation, apoptosis and immune processes, inflammation, cancer, arthritis, asthma, diabetes, and other diseases. This review attempts to summarize the current status of natural products and their derivatives (2002-2013) regulating the proteins or transcription elements of JAK/STAT signaling pathway to supply a new direction or drug targets for the discovery of new drugs.
Topics: Biological Products; Drug Discovery; Humans; Janus Kinases; Molecular Structure; Signal Transduction
PubMed: 25076196
DOI: 10.1080/10286020.2014.929573 -
Leukemia & Lymphoma 2015Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life... (Review)
Review
Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life expectancy. Dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is prominent, even in the absence of the JAK2(V617F) mutation. Therefore, all symptomatic MF patients may potentially derive benefit from JAK inhibitors. Despite the efficacy of JAK inhibitors in controlling signs and symptoms of MF, they do not eradicate the disease. Therefore, JAK inhibitors are currently being tested in combination with other novel therapies, a strategy which may be more effective in reducing disease burden, either by overcoming JAK inhibitor resistance or targeting additional mechanisms of pathogenesis. Additional targets include modulators of epigenetic regulation, pathways that work downstream from JAK/STAT (i.e. mammalian target of rapamycin/AKT/phosphoinositide 3-kinase) heat shock protein 90, hedgehog signaling, pro-fibrotic factors, abnormal megakaryocytes and telomerase. In this review, we discuss novel MF therapeutic strategies.
Topics: Animals; Drug Resistance; Gene Expression Regulation; Humans; Janus Kinases; Molecular Targeted Therapy; Mutation; Nuclear Proteins; Primary Myelofibrosis; Promyelocytic Leukemia Protein; Protein Kinase Inhibitors; STAT Transcription Factors; Signal Transduction; Transcription Factors; Tumor Suppressor Proteins
PubMed: 25860240
DOI: 10.3109/10428194.2015.1037762 -
Frontiers in Immunology 2024Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with... (Review)
Review
Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with biologics treatment. Paradoxical reaction through immune-related dermatoses refer to the new onset or exacerbation of other immune-mediated dermatoses (mainly psoriasis and atopic dermatitis) after biologics treatment of inflammatory dermatoses (mainly psoriasis and atopic dermatitis), such as new atopic dermatitis (AD) in psoriasis (PsO) treatment and new PsO in AD treatment. A common genetic background and Inflammatory pathway are possible pathogenesis. Faced with paradoxical reactions, the choice of therapy needs to be directed toward therapies effective for both diseases, such as Janus kinase (JAK) inhibitors. The Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway plays an important role in the inflammatory pathway, and has been widely used in the treatment of AD and PsO in recent years. This article focuses on JAK inhibitors such as tofacitinib, baricitinib, ruxolitinib, Abrocitinib, upadacitinib, and deucravacitinib, to explore the possible application in treatment of paradoxical reactions. Common side effects, baseline risk factors and safety use of JAK inhibitors were discussed.
Topics: Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Psoriasis; Biological Products; Janus Kinases
PubMed: 38444845
DOI: 10.3389/fimmu.2024.1341632