R788 is a prodrug of the active compound tamatinib (R-406), which is an inhibitor of the enzyme spleen tyrosine kinase (Syk). R788 (Fostamatinib) effectively inhibits BCR signaling in vivo, resulting in reduced proliferation and survival of the malignant B cells and significantly prolonged survival of the treated animals. R788 also inhibits the anti-IgE-induced production and release of LTC4 and cytokines and chemokines, including TNFα, IL-8 and GM-CSF. R788 (Fostamatinib) induces apoptosis of the majority of examined DLBCL cell lines. Fostamatinib is orally bioavailable and was well tolerated in phase I and II trials, with the most common side effect being gastrointestinal symptoms. Fostamatinib is currently in phase III clinical trials for rheumatoid arthritis and phase II trials for autoimmune thrombocytopenia and lymphoma.
|Cell lines||Cultured human mast cells (CHMC)|
|Preparation method||Human Mast Cell Culture and Stimulation.
Cultured human mast cells (CHMC) were derived from cord blood CD34+ progenitor cells and grown, primed, and stimulated as described previously (Rossi et al., 2006) and shown in supplemental data. Before stimulation, cells were incubated with R406 or DMSO for 30 min. Cells were then stimulated with either 0.25 to 2 mg/ml anti-IgE or anti-IgG or 2 μM ionomycin. For tryptase measurement, ∼1500 cells per well were stimulated for 30 min in modified Tyrode's buffer. For LTC4 and cytokine production, 100,000 cells per well were stimulated for 1 or 7 h, respectively. Tryptase activity was measured by luminescence readout of a peptide substrate, and LTC4 and cytokines were measured using Luminex multiplex technology.
|Incubation time||30 min|
|Animal models||K/BxN Model Arthritis induced in C57BL/6 mice|
|Formulation||35% TPGS, 60% PEG 400, and 5% propylene glycol|
|Dosages||5 and 10mg/kg b.i.d for 13 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 110 mg/mL|
|Source||Blood (2010). Figure 2.R788|
|Cell Lines||TCL1 leukemia cells|
|Incubation Time||24, 48, and 72 h|
|Results||As shown in Figure 2, a modest decrease in the percentage of viable (annexin V/PI negative) cells was observed at the highest R406 concentrations.|
The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling.
Suljagic M, et al. Blood. 2010 Dec 2;116(23):4894-905. PMID: 20716772.
Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases.
Bajpai M. IDrugs. 2009 Mar;12(3):174-85. PMID: 19333898.
R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation.
Braselmann S, et al. J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008. PMID: 16946104.
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Piceatannol, a natural stilbene, is a selective Syk inhibitor and ~10-fold selectivity versus Lyn.
GS-9973 is an orally bioavailable, selective Syk inhibitor with IC50 of 7.7 nM.
P505-15 (PRT062607) is a novel, highly selective inhibitor of Syk with IC50 value of 1-2 nM.
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