Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Spleen tyrosine kinase (Syk), a 72 KDa cytosolic non-receptor tyrosine kinase is a key mediator of B cell receptor (BCR) and Fc receptor (FcR) signalling in a variety of inflammatory cell types and has been implicated in the pathogenesis of a number of allergic and autoimmune diseases including Asthma, Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). Several Syk inhibitors are currently in clinical development and here we report an extended pharmacological and biological profile of GSK143 a novel, highly selective, orally bio-available Syk inhibitor.
Methods:
GSK143 inhibitory activity (dose range 10uM to 1nM) on BCR signalling was evaluated in human and murine whole blood by assessing the cell surface expression of IgM stimulated CD69 using flow cytometry. IgM antibody titres in a 7 day murine T independent immunisation model, induced by a TNP-ficol challenge, were measured after once daily dosing (5, 10, 15 and 30mg/kg) to determine in-vivo activity. The effect of GSK143 (dose range 10uM to 10nM) on TNFa production was explored in human monocytic cells, from 8 donors, differentiated to a pro-inflammatory M1 macrophage phenotype with GM-CSF. Macrophages were stimulated with Ig-conjugated sepharose beads to mimic immune complex activation of the Fc gamma receptor (FcγR).
Results:
GSK143 dose dependently inhibited the IgM stimulated CD69 expression in both human and murine whole blood with IC50s of 185nM (pIC50 6.734 +/- 0.06) and 364nM (pIC50 6.44 +/-0.28) respectively. In the murine model of T cell independent immunisation, GSK143 administered orally once daily (qd) from day 1 to day 6, produced a significant reduction in the concentration of IgM antibodies (ng/mL) in comparison to that of the corresponding vehicle control group (22843.11 ± 3377.88 ng/mL) vs (15484.62 ± 1984.15 ng/mL, P < 0.01)), (11135.83 ± 2129.6 ng/mL, P < 0.001), (5919.73 ± 1539.03 ng/mL, P < 0.001) and (2877.67 ± 722.79 ng/mL, P < 0.001) at the 5, 10, 15 and 30 mg/kg doses respectively. The systemic exposure observed on day 6 increased with the administered dose with AUC0-24h (ng.h/mL) values of 1435.3 ± 808.2 ng.h/mL, 2457.1 ± 640.1 ng.h/mL, 5533.6 ± 2772.4 ng.h/mL and 7901.7 ± 3058.7 ng.h/mL for the 5, 10, 15 and 30 mg/kg doses, respectively. In human GM-CSF differentiated macrophages stimulated with Ig conjugated beads, GSK143 inhibited FcγR mediated TNFa release in a concentration dependent manner (IC50 = 34nM, pIC50 of 7.47 +/- 0.31).
Conclusion:
GSK143, a potent, highly selective and orally bio-available Syk inhibitor blocked FcγR and BCR signalling in pre-clinical human and rodent in-vitro and in-vivo models of inflammatory and autoimmune diseases.
Disclosure:
M. C. Dickson,
GSK,
3;
N. Smithers,
GSK,
3;
H. Lewis,
GSK,
3;
C. Ramirez-Molina,
GSK,
3;
S. McCleary,
GSK,
3;
M. Barker,
GSK,
3;
J. Liddle,
GSK,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-potent-highly-selective-and-orally-bioavailable-spleen-tyrosine-kinase-inhibitor-gsk143-demonstrates-efficacy-in-b-cell-receptor-and-fc-receptor-signalling-in-models-of-inflammatory-and-autoimmun/