Abstract
Spleen tyrosine kinase (Syk) is a critical target protein for treating immunoreceptor signalling-mediated allergies. In this study, a virtual screening of an in-house Chinese medicine database followed by biological assays was carried out to identify novel Syk inhibitors. A molecular docking method was employed to screen for compounds with potential Syk inhibitory activity. Then, an in vitro kinase inhibition assay was performed to verify the Syk inhibitory activity of the virtual screening hits. Subsequently, a β-hexosaminidase release assay was conducted to evaluate the anti-mast cell degranulation activity of the active compounds. Finally, tanshinone I was confirmed as a Syk inhibitor (IC50 = 1.64 μM) and exhibited anti-mast cell degranulation activity in vitro (IC50 = 2.76 μM). Docking studies showed that Pro455, Gln462, Leu377, and Lys458 were key amino acid residues for Syk inhibitory activity. This study demonstrated that tanshinone I is a Syk inhibitor with mast cell degranulation inhibitory activity. Tanshinone I may be a potential lead compound for developing effective and safe Syk-inhibiting drugs.
Highlights
Spleen tyrosine kinase (Syk) is a 72 kDa cytosolic non-receptor tyrosine kinase that is involved in signal transduction by the classic immunoreceptors, including mast cells, B-lymphocytes, and macrophages, and contributes to diverse cellular responses, including histamine release, cell proliferation, differentiation, and phagocytosis [1].Studies have shown that when stimulated through FcεRI, Syk-deficient mast cells cannot synthesize leukotrienes, secrete cytokines, or degranulate [2]
We carried out a virtual screening of an in-house Chinese medicine database to identify a novel scaffold for Syk inhibitors
The results presented here led us to conclude that tanshinone I is an active inhibitor against Syk
Summary
Spleen tyrosine kinase (Syk) is a 72 kDa cytosolic non-receptor tyrosine kinase that is involved in signal transduction by the classic immunoreceptors, including mast cells, B-lymphocytes, and macrophages, and contributes to diverse cellular responses, including histamine release, cell proliferation, differentiation, and phagocytosis [1].Studies have shown that when stimulated through FcεRI, Syk-deficient mast cells cannot synthesize leukotrienes, secrete cytokines, or degranulate [2]. Spleen tyrosine kinase (Syk) is a 72 kDa cytosolic non-receptor tyrosine kinase that is involved in signal transduction by the classic immunoreceptors, including mast cells, B-lymphocytes, and macrophages, and contributes to diverse cellular responses, including histamine release, cell proliferation, differentiation, and phagocytosis [1]. Inhibition of Syk-mediated immunoreceptor (B-cell receptors, T-cell receptors and Fc receptors) signalling leads to inhibition of mast cells, macrophages and B-cell activation and subsequent release of inflammatory modulators [3]. Buyanravjikh et al reported that cryptotanshinone could inhibit IgE-mediated mast cell degranulation through theinhibition of tyrosine kinase-dependent degranulation signalling pathways involving Syk and Lyn [4]. Seeking safe Syk small molecule inhibitors has attracted considerable interest in a number of therapeutic areas, including the treatment of allergic asthma, rhinitis, rheumatoid arthritis and chronic lymphocytic leukaemia [5,6,7]. There is currently no Syk small molecule inhibitor drug on the market, some potential compounds have been tested in clinical trials [8,9]
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