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| 25mg |
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Purity: ≥98%
Fostamatinib disodium hexahydrate (formerly R-935788; R 935788; R-788; R788; trade name: Tavalisse) is the disodium salt and hexa-hydrated form of Fostamatinib which is a prodrug of the active metabolite R406. In order to treat thrombocytopenia in adult patients with persistent or chronic immune thrombocytopenia (ITP), the FDA approved the oral bioactive and selective Syk inhibitor fostamatinib in 2018. Using a 41 nM IC50 in a cell-free assay, it inhibits Syk kinase.
| Targets |
Syk (IC50 = 41 nM)
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| ln Vitro |
R406, a spleen tyrosine kinase (Syk) inhibitor, is prodrugged by R788. R788 has a Ki of 30 nM and functions as a competitive inhibitor of ATP binding. With an EC50 of 56 nM, R788 dose-dependently prevents anti-IgE-mediated CHMC degranulation. R788 also prevents the release of LTC4 and cytokines and chemokines, such as TNFα, IL-8, and GM-CSF, that are triggered by anti-IgE. All phosphorylation events downstream of Syk signaling are inhibited when R788 inhibits Syk. The most potent inhibitor of IL-4 and IL-2 receptor signaling in CHMC is R788, followed by FcρRI signaling. R788 specifically inhibits human mast cells, neutrophils, and macrophages' FcγR signaling. R788 has the ability to prevent immune complex-mediated local inflammatory injury.R788 causes most of the tested DLBCL cell lines to undergo apoptosis[1]. R788 selectively inhibits both tonic- and ligand-induced BCR signaling (autophosphorylation of SYK525/526 and SYK-dependent phosphorylation of the B-cell linker protein [BLNK]) in R788-sensitive DLBCL cell lines[2].
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| ln Vivo |
R788 administered orally to mice decreases immune complex-mediated inflammation in two antibody-induced arthritis models and a reverse-passive Arthus reaction.[1] Another study found that R788 significantly increases the survival of treated animals while also effectively inhibiting BCR signaling in vivo, which reduces the proliferation and survival of malignant B cells. [3] In rheumatoid arthritis models, R788 shows a marked decrease in key inflammatory mediators like TNFalpha, IL-1, IL-6, and IL-18, which results in less inflammation and bone degradation.[4]
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| Enzyme Assay |
There are fluorescence polarization reactions. In order to determine Ki, eight distinct ATP concentrations are set up in duplicate 200-μL reactions, starting at 200 μM (2-fold serial dilutions), with or without DMSO or R788 at 125, 62.5, 31.25, 15.5, or 7.8 nM. Twenty microliters of each reaction are taken out and quenched at various times to bring the reaction to an end. Plotting the rate of reaction against the ATP concentration yields the apparent Km and Vmax for each concentration of R788. To calculate the Ki, the apparent Km (or apparent Ki/Vmax) is finally plotted against the inhibitor concentration.
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| Cell Assay |
Complementary data shows the growth, priming, and stimulation of cultured human mast cells (CHMC), which are derived from cord blood CD34+ progenitor cells. Cells are cultivated in DMSO or R788 for half an hour prior to stimulation. The next step involves stimulating the cells using either 2 μM ionomycin or 0.25 to 2 mg/mL anti-IgE or anti-IgG. A modified Tyrode's buffer is used to stimulate approximately 1500 cells per well for 30 minutes in order to measure tryptase. Ten thousand cells per well are stimulated for one hour for LTC4 production and seven hours for cytokine production. LTC4 and cytokines are detected using Luminex multiplex technology, while tryptase activity is determined by luminescence readout of a peptide substrate.
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| Animal Protocol |
Balb/c mice with arthritis
1 mg/kg or 5 mg/kg o.g. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation No information is available on the clinical use of fostamatinib during breastfeeding. Because the active metabolite of fostamatinib (R406) is 98.3% bound to plasma proteins, the amount in milk is likely to be low. However, the active metabolites has a half-life of 15 hours, and might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during fostamatinib therapy and for at least 1 month after the final dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
| References | |
| Additional Infomation |
Fostamatinib Disodium is an orally available disodium salt of the Syk kinase inhibitor fostamatinib with potential anti-inflammatory and immunomodulating activities. Fostamatinib inhibits Syk kinase-mediated IgG Fc gamma receptor signaling, resulting in inhibition of the activation of mast cells, macrophages, and B-cells and related inflammatory responses and tissue damage. Syk kinase, widely expressed in hematopoietic cells, is a nonreceptor tyrosine kinase that is involved in coupling activated immunoreceptors to signal downstream events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis.
See also: Fostamatinib Disodium (annotation moved to). Drug Indication Tavlesse is indicated for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments. |
| Molecular Formula |
C₂₃H₂₄FN₆NA₂O₉P.₆H₂O
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|---|---|---|
| Molecular Weight |
732.51
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| Exact Mass |
732.18
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| Elemental Analysis |
C, 37.71; H, 4.95; F, 2.59; N, 11.47; Na, 6.28; O, 32.76; P, 4.23
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| CAS # |
914295-16-2
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| Related CAS # |
Fostamatinib Disodium;1025687-58-4;Fostamatinib;901119-35-5
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| PubChem CID |
24828759
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| Appearance |
White to gray solid powder
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| LogP |
3.241
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
21
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
48
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| Complexity |
893
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| Defined Atom Stereocenter Count |
0
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| SMILES |
[Na].O=C1C(C)(C)OC2C(=NC(NC3C(F)=CN=C(NC4C=C(OC)C(OC)=C(OC)C=4)N=3)=CC=2)N1COP(O)(O)=O.O.[Na].O.O.O.O.O
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| InChi Key |
ZQGJCHHKJNSPMS-UHFFFAOYSA-L
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| InChi Code |
InChI=1S/C23H26FN6O9P.2Na.6H2O/c1-23(2)21(31)30(11-38-40(32,33)34)20-14(39-23)6-7-17(28-20)27-19-13(24)10-25-22(29-19)26-12-8-15(35-3)18(37-5)16(9-12)36-4;;;;;;;;/h6-10H,11H2,1-5H3,(H2,32,33,34)(H2,25,26,27,28,29);;;6*1H2/q;2*+1;;;;;;/p-2
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| Chemical Name |
disodium;[6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl phosphate;hexahydrate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 8.33 mg/mL (11.37 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 10 mg/mL (13.65 mM) in Cremophor EL (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. View More
Solubility in Formulation 3: 0.5% CMC+0.25% Tween 80,pH6.5: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3652 mL | 6.8258 mL | 13.6517 mL | |
| 5 mM | 0.2730 mL | 1.3652 mL | 2.7303 mL | |
| 10 mM | 0.1365 mL | 0.6826 mL | 1.3652 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00798096 | Completed | Drug: Fostamatinib Disodium | T Cell Lymphoma | Rigel Pharmaceuticals | March 2009 | Phase 2 |
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