Fostamatinib (R788) is a precursor 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.
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Source | Blood (2010). Figure 2.R788 |
| Method | apoptosis assay | |
| Cell Lines | TCL1 leukemia cells | |
| Concentrations | 10 μM | |
| 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. |
| Cell Experiment | |
|---|---|
| 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. |
| Concentrations | 0~20 μM |
| Incubation time | 30 min |
| Animal Experiment | |
|---|---|
| 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 |
| Administration | orally |
| Molecular Weight | 580.46 |
| Formula | C23H26FN6O9P |
| CAS Number | 901119-35-5 |
| Solubility (25°C) | DMSO 60 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
| Related Syk Products |
|---|
| Syk Kinase Peptide Substrate
Syk Kinase Peptide Substrate is a Syk kinase peptide substrate. |
| TOP1288
TOP1288 is an SRC/Syk/p38α inhibitor for studies related to ulcerative colitis. |
| R343
R343 is an immunoglobulin E (IgE) as well as spleen tyrosine kinase (Syk) inhibitor for studies related to allergic asthma and non-small cell lung cancer. |
| R333
R333 is a JAK/SYK inhibitor that can be used in studies related to discoid lupus erythematosus (DLE). |
| PRT2761
PRT2761 is a spleen tyrosine kinase (Syk) inhibitor that may be used in studies related to allergic conjunctivitis. |
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