Fostamatinib (R788)

Catalog No.S2625

Fostamatinib (R788), a prodrug of the active metabolite R406, is a Syk inhibitor with IC50 of 41 nM, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. Phase 3.

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Fostamatinib (R788) Chemical Structure

Fostamatinib (R788) Chemical Structure
Molecular Weight: 580.46

Validation & Quality Control

Quality Control & MSDS

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Fostamatinib (R788) is available in the following compound libraries:

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Product Description

Biological Activity

Description Fostamatinib (R788), a prodrug of the active metabolite R406, is a Syk inhibitor with IC50 of 41 nM, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. Phase 3.
Targets Syk [1] Adenosine A3 receptor [1] Adenosine transporter [1] Monoamine transporter [1]
IC50 41 nM 81 nM 1.84 μM 2.74 μM
In vitro R788 is a prodrug of the spleen tyrosine kinase (Syk) inhibitor R406. R788 is a competitive inhibitor for ATP binding with a Ki of 30 nM. R788 dose-dependently inhibits anti-IgE-mediated CHMC degranulation with an EC50 of 56 nM. R788 also inhibits the anti-IgE-induced production and release of LTC4 and cytokines and chemokines, including TNFα, IL-8, and GM-CSF. Inhibition of Syk by R788 results in inhibition of all phosphorylation events downstream of Syk signaling. Next to FcϵRI signaling in CHMC, R788 most potently inhibits the signaling of IL-4 and IL-2 receptors. R788 specifically inhibits FcγR signaling in human mast cells, macrophages, and neutrophils. R788 can inhibit local inflammatory injury mediated by immune complexes. [1] R788 induces apoptosis of the majority of examined DLBCL cell lines. In R788-sensitive DLBCL cell lines, R788 specifically inhibits both tonic- and ligand-induced BCR signaling (autophosphorylation of SYK525/526 and SYK-dependent phosphorylation of the B-cell linker protein [BLNK]). [2]
In vivo Oral administration of R788 to mice reduces immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. [1] In another study, R788 effectively inhibits BCR signaling in vivo, resulting in reduced proliferation and survival of the malignant B cells and significantly prolongs survival of the treated animals. [3] R788 demonstrates a significant reduction in major inflammatory mediators such as TNFalpha, IL-1, IL-6 and IL-18, leading to reduced inflammation and bone degradation in models of rheumatoid arthritis. [4]
Features Converted into its active metabolite R406 in vivo.

Protocol(Only for Reference)

Kinase Assay:

[1]

Fluorescence polarization kinase assay and Ki determination The fluorescence polarization reactions are performed. For Ki determination, duplicate 200-μL reactions are set up at eight different ATP concentrations from 200 μM (2-fold serial dilutions) in the presence of either DMSO or R788 at 125, 62.5, 31.25, 15.5, or 7.8 nM. At different time points, 20 μL of each reaction is removed and quenched to stop the reaction. For each concentration of R788, the rate of reaction at each concentration of ATP is determined and plotted against the ATP concentration to determine the apparent Km and Vmax (maximal rate). Finally the apparent Km (or apparent Ki/Vmax) is plotted against the inhibitor concentration to determine the Ki.

Cell Assay:

[1]

Cell lines Cultured human mast cells (CHMC)
Concentrations 0 μM -100 μM
Incubation Time 30 minutes
Method

Cultured human mast cells (CHMC) are derived from cord blood CD34+ progenitor cells and grown, primed, and stimulated and shown in supplemental data. Before stimulation, cells are incubated with R788 or DMSO for 30 minutes. Cells are 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 are stimulated for 30 min in modified Tyrode's buffer. For LTC4 and cytokine production, 100,000 cells per well are stimulated for 1 or 7 hours, respectively. Tryptase activity is measured by luminescence readout of a peptide substrate, and LTC4 and cytokines are measured using Luminex multiplex technology.

Animal Study:

[1]

Animal Models Balb/c mice with arthritis
Formulation 35% TPGS, 60% PEG 400, 5% propylene glycol
Dosages 1 mg/kg or 5 mg/kg
Administration Orally b.i.d

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Braselmann S, et al. J Pharmacol Exp Ther, 2006, 319(3), 998-1008.

[2] Chen L et al.Blood, 2008, 111(4), 2230-2237.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-05-07)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02612558 Recruiting Warm Antibody Autoimmune Hemolytic Anemia Rigel Pharmaceuticals April 2016 Phase 2
NCT02611063 Recruiting Hematological Malignancies Stefanie Sarantopoulos, MD, PhD.|Duke University January 2016 Phase 1
NCT02433236 Withdrawn IGA Nephropathy Rigel Pharmaceuticals September 2015 Phase 2
NCT02076412 Active, not recruiting Immune Thrombocytopenic Purpura Rigel Pharmaceuticals November 2014 Phase 3
NCT02112838 Recruiting IGA Nephropathy Rigel Pharmaceuticals October 2014 Phase 2

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Chemical Information

Download Fostamatinib (R788) SDF
Molecular Weight (MW) 580.46
Formula

C23H26FN6O9P

CAS No. 901119-35-5
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 116 mg/mL (199.84 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 4% DMSO+30% PEG 300+ddH2O 5mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2,3-dihydropyrido[3,2-b][1,4]oxazin-4-yl)methyl dihydrogen phosphate

Tech Support

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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