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.
Highlights
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
Selectivity of RO9021 against a panel of 451 wild-type and mutant protein kinases was assessed using an ATP binding site competition assay developed by KINOMEscan Inc. [3]
The selectivity of RO9021 was quantitatively expressed as a selective score (S-score), which was calculated by dividing the number of RO9021-bound kinases by the total number of wild-type protein kinases tested (n = 392), excluding mutant variants
Summary
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. In the case of rheumatoid arthritis (RA) pathogenesis, the critical role of the adaptive immune response and proinflammatory cytokines has been unequivocally established by the efficacy of marketed biologics targeting tumor necrosis factor (TNF) alpha, interleukin (IL)-6, CD20 (B-cell depletion) and CD80/86 (modulation of T-cell co-stimulation) Their efficacy are capped by limited efficacy, with 40% of patients never responding to treatments and only 20% of patients experiencing a major reduction in disease activity [1]. For other autoimmune diseases that are in dire need of safer and/or more effective therapies, the antiBAFF antibody belimumab, despite showing marginal efficacy in clinical trials, was approved for treatment of systemic lupus erythematous (SLE) Another anti-BAFF antibody (tabalumab) did not show adequate efficacy in a phase 3 RA trial (Elli Lilly news release, 13 December 2012). Whether an agent that neutralizes both BAFF and APRIL will produce better results remains to be seen
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