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Formula | C21H22N8O2 |
Molar mass | 418.461 g·mol−1 |
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Z583 (GLXC-26150) is a chemical compound which acts as a potent and highly selective inhibitor of JAK3, and was developed for the treatment of rheumatoid arthritis. [1] [2] [3] [4] [5]
Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2, but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.
Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. It can be given by mouth or by injection.
The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.
Cytotoxic T-lymphocyte associated protein 4, (CTLA-4) also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. It is encoded by the gene CTLA4 in humans.
A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.
Interleukin 24 (IL-24) is a protein in the interleukin family, a type of cytokine signaling molecule in the immune system. In humans, this protein is encoded by the IL24 gene.
Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.
Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the JAK3 gene.
Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.
T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.
Interleukin 20 receptors (IL20R) belong to the IL-10 family. IL20R are involved in both pro-inflammatory and anti-inflammatory immune response. There are two types of IL20R: Type I and Type II.
Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.
John J. O'Shea is an American physician and immunologist.
A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.
Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. It is a janus kinase (JAK) inhibitor, discovered and developed by the National Institutes of Health and Pfizer.
Blisibimod is a selective antagonist of B-cell activating factor, being developed by Anthera Pharmaceuticals as a treatment for systemic lupus erythematosus. It is currently under active investigation in clinical trials.
Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis (RA). It was developed by the Belgian-Dutch biotech company Galapagos NV.
Upadacitinib, sold under the brand name Rinvoq, is a medication used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis. Upadacitinib is a Janus kinase (JAK) inhibitor that works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.
Janus kinase 3 inhibitors, also called JAK3 inhibitors, are a new class of immunomodulatory agents that inhibit Janus kinase 3. They are used for the treatment of autoimmune diseases. The Janus kinases are a family of four nonreceptor tyrosine-protein kinases, JAK1, JAK2, JAK3, and TYK2. They signal via the JAK/STAT pathway, which is important in regulating the immune system. Expression of JAK3 is largely restricted to lymphocytes, while the others are ubiquitously expressed, so selective targeting of JAK3 over the other JAK isozymes is attractive as a possible treatment of autoimmune diseases.
Decernotinib is an inhibitor of Janus kinase 3 (JAK3) discovered through a process of inhouse screening of a chemical compound library. Decernotinib also had the name VX-509 in development phase. It is an experimental drug with high selectivity for JAK3, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). It has been studied in clinical trials at Vertex Pharmaceuticals, and while it was not approved for clinical use it continues to be used for research.