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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.
- Source :
-
Arthritis research & therapy [Arthritis Res Ther] 2013 Oct 04; Vol. 15 (5), pp. R146. Date of Electronic Publication: 2013 Oct 04. - Publication Year :
- 2013
-
Abstract
- Introduction: Spleen 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.<br />Methods: A SYK inhibitor was developed and assayed in various in vitro systems and in the mouse model of collagen-induced arthritis (mCIA).<br />Results: A 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.<br />Conclusions: Inhibition 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.
- Subjects :
- Administration, Oral
Aminopyridines chemistry
Aminopyridines pharmacology
Animals
Arthritis, Experimental metabolism
Arthritis, Experimental prevention & control
Autoimmune Diseases drug therapy
Autoimmune Diseases metabolism
B-Lymphocytes drug effects
B-Lymphocytes immunology
B-Lymphocytes metabolism
Cell Line, Tumor
Cells, Cultured
Flow Cytometry
Humans
Intracellular Signaling Peptides and Proteins chemistry
Intracellular Signaling Peptides and Proteins metabolism
Jurkat Cells
Macrophages cytology
Macrophages drug effects
Macrophages metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Models, Molecular
Molecular Structure
Osteoclasts cytology
Osteoclasts drug effects
Osteoclasts metabolism
Protein Binding
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors chemistry
Protein Structure, Tertiary
Protein-Tyrosine Kinases chemistry
Protein-Tyrosine Kinases metabolism
Pyridazines chemistry
Pyridazines pharmacology
Signal Transduction drug effects
Small Molecule Libraries administration & dosage
Small Molecule Libraries chemistry
Syk Kinase
Adaptive Immunity drug effects
Immunity, Innate drug effects
Intracellular Signaling Peptides and Proteins antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Protein-Tyrosine Kinases antagonists & inhibitors
Small Molecule Libraries pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1478-6362
- Volume :
- 15
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Arthritis research & therapy
- Publication Type :
- Academic Journal
- Accession number :
- 24286216
- Full Text :
- https://doi.org/10.1186/ar4329