ArticleArthritis research & therapy2013
Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy.
Article in Arthritis research & therapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 46 citations in OpenAlex.
- Spleen tyrosine kinase (SYK) signals are implicated in cardio-cerebrovascular diseases.Heliyon · 2023Review
- Correlation between IL3 signaling pathway-related genes and immune checkpoint inhibitor efficacy in patients with renal cell carcinoma.Cancer biomarkers : section A of Disease markers · 2023Article
- Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition.International journal of molecular sciences · 2022Article
- CD4Epigenetics · 2022Article
- Identifying RO9021 as a Potential Inhibitor of PknG fromACS omega · 2022Article
- Semi-Mechanistic PK/PD Modeling and Simulation of Irreversible BTK Inhibition to Support Dose Selection of Tirabrutinib in Subjects with RA.Clinical pharmacology and therapeutics · 2022Article
- Biological Effects of β-Glucans on Osteoclastogenesis.Molecules (Basel, Switzerland) · 2021Review
- Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases.ACS medicinal chemistry letters · 2020Article
- Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases.Frontiers in immunology · 2019Review
- The role of Syk in peripheral T cells.Clinical immunology (Orlando, Fla.) · 2018Article
- Macrophages and the Recovery from Acute and Chronic Inflammation.Annual review of physiology · 2017Review
- Investigation into the Role of PI3K and JAK3 Kinase Inhibitors in Murine Models of Asthma.Frontiers in pharmacology · 2017Article
- Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.ACS medicinal chemistry letters · 2016Article
- Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis.Journal of immunology (Baltimore, Md. : 1950) · 2016Article
- Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice.Alcoholism, clinical and experimental research · 2016Article
- 1-(2,3-Dibenzimidazol-2-ylpropyl)-2-methoxybenzene Is a Syk Inhibitor with Anti-Inflammatory Properties.Molecules (Basel, Switzerland) · 2016Article
- A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation.PloS one · 2016Article
- The plasmacytoid dendritic cell as the Swiss army knife of the immune system: molecular regulation of its multifaceted functions.Journal of immunology (Baltimore, Md. : 1950) · 2014Review
- Cutting edge: the UNC93B1 tyrosine-based motif regulates trafficking and TLR responses via separate mechanisms.Journal of immunology (Baltimore, Md. : 1950) · 2014Article
- Getting Syk: spleen tyrosine kinase as a therapeutic target.Trends in pharmacological sciences · 2014Review
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Authors and funding
19 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionSpleen tyrosine kinase (SYK) is a key integrator of intracellular signals triggered by activated immunoreceptors, including Bcell receptors (BCR) and Fc receptors, which are important for the development and function of lymphoid cells. Given the clinical efficacy of Bcell depletion in the treatment of rheumatoid arthritis and multiple sclerosis, pharmacological modulation of Bcells using orally active small molecules that selectively target SYK presents an attractive alternative therapeutic strategy.
methodsA SYK inhibitor was developed and assayed in various in vitro systems and in the mouse model of collagen-induced arthritis (mCIA).
resultsA novel ATP-competitive inhibitor of SYK, 6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide, designated RO9021, with an adequate kinase selectivity profile and oral bioavailability, was developed. In addition to suppression of BCR signaling in human peripheral blood mononuclear cells (PBMC) and whole blood, FcγR signaling in human monocytes, and FcϵR signaling in human mast cells, RO9021 blocked osteoclastogenesis from mouse bone marrow macrophages in vitro. Interestingly, Toll-like Receptor (TLR) 9 signaling in human Bcells was inhibited by RO9021, resulting in decreased levels of plasmablasts, immunoglobulin (Ig) M and IgG upon B-cell differentiation. RO9021 also potently inhibited type I interferon production by human plasmacytoid dendritic cells (pDC) upon TLR9 activation. This effect is specific to TLR9 as RO9021 did not inhibit TLR4- or JAK-STAT-mediated signaling. Finally, oral administration of RO9021 inhibited arthritis progression in the mCIA model, with observable pharmacokinetics (PK)-pharmacodynamic (PD) correlation.
conclusionsInhibition of SYK kinase activity impinges on various innate and adaptive immune responses. RO9021 could serve as a starting point for the development of selective SYK inhibitors for the treatment of inflammation-related and autoimmune-related disorders.
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