R788 (Fostamatinib) Disodium

Catalog No.S2206 Synonyms: Tamatinib Fosdium

R788 (Fostamatinib) Disodium Chemical Structure

Molecular Weight(MW): 624.42

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

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Cited by 3 Publications

1 Customer Review

  • BCWM.1 and MWCL-1 cells treated with either vehicle or fostamatinib at the indicated concentrations for two hours, then protein extracts were analyzed by Western blotting for the activation status of MEK, p44/42 MAPK, and Akt with phospho-specific antibodies.

    Clin Cancer Res, 2015, 21(11): 2538-45. R788 (Fostamatinib) Disodium purchased from Selleck.

Purity & Quality Control

Choose Selective Syk Inhibitors

Biological Activity

Description R788 (Fostamatinib) disodium, a prodrug of the active metabolite R406, is a Syk inhibitor with IC50 of 41 nM in a cell-free assay, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. Phase 3.
Features Clinically used oral formulation of R406.
Targets
Syk [1]
(Cell-free assay)
41 nM
In vitro

R935788 is a methylene phosphate prodrug of R406, which can be rapidly converted to R406 in vivo. R406 (in vitro active form of R935788) selectively inhibits Syk-dependent signaling with EC50 values ranging from 33 nM to 171 nM, more potently than Syk-independent pathways in different cells. [1] R406 inhibits cellular proliferation of a variety of diffuse large B-cell lymphoma (DLBCL) cell lines with EC50 values ranging from 0.8 μM to 8.1 μM. [2] R406 treatment reduces basal phosphorylation of BLNK, Akt, glycogen synthase kinase-3 (GSK-3), forkhead box O (FOXO) and ERK not only in cells with high (TCL-002) but also in cells with low levels of phosphorylated Syk (TCL1-551). In addition, R406 completely inhibits the anti-IgM induced Bcr signal in TCL1 leukemias. Despite the higher levels of constitutively active Syk in TCL1 leukemias, R406 is not selectively cytotoxic to the leukemic cells. [3]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human Ramos cells MUfDfZRwfG:6aXRCpIF{e2G7 M4LDNmN6fG:2b4jpZ4l1gSCjZ3HpcpN1KGi3bXHuJHJidW:|IHPlcIx{NCCLQ{WwQVAvOjZ5IN88US=> Mlu1NlMyPTFyNUS=

... Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Western blot
p-JAK2 / JAK2 / p-SRC / SRC / p-FAK / FAK / p-SYK / SYK / p-ERK / ERK; 

PubMed: 29340070     


SKLB-850 inhibited Syk/ERK, Src/FAK and JAK2/STAT3 signaling pathways. The Ramos cells were incubated for 24 hours in medium containing vehicle, SKLB-850, or R788, and then lysed for western blot assay. 

p-SYK(525-526) / t-SYK / p-SYK(323) / p-BTK / t-BTK; 

PubMed: 25748087     


BCWM.1 and MWCL-1 cells treated with either vehicle or fostamatinib at the indicated concentrations for two hours were harvested and lysed, and protein extracts were analyzed by Western blotting. The activation status of Syk (A, B) and BTK (C) was probed with phospho-specific antibodies using β-Actin as well as the levels of total, non-phosphorylated Syk and BTK as controls. Data shown are representative of one of three independent experiments.

p-MEK / MEK / p-ERK / ERK / p-AKT / AKT; 

PubMed: 25748087     


BCWM.1 and MWCL-1 cells treated with either vehicle or fostamatinib at the indicated concentrations for two hours were harvested and lysed. Protein extracts were analyzed by Western blotting for the activation status of MEK, p44/42 MAPK, and Akt with phospho-specific antibodies as described earlier.

29340070 25748087
Growth inhibition assay
Cell viability; 

PubMed: 25748087     


BCWM.1 (A) and MWCL-1 cells (B) were seeded in 96 wells plates at 10,000 cells per well and treated with vehicle, 0.25, or 1 μM concentrations of fostamatinib for 24, 48, or 72 hours, as indicated. Cell viability was assayed using the tetrazolium reagent WST-1, and data shown are representative of one of two independent experiments, each performed in triplicate, and are presented as mean ± S.D. A “**” indicates a statistical significance at a level of p < 0.01 compared to vehicle-treated controls using the student’s t-test.

25748087
In vivo Given that plasma half-life of R406 in mice is less than 2 hours, R935788 is administered in 3 divided doses at 3-hour intervals to provide continuous Syk inhibition during each day of treatment, mimicking the longer plasma half-life in humans (15 hours). Despite the relatively modest cytotoxic effect in vitro, R935788 significantly inhibits the proliferation and survival of leukemic cell in vivo, which is associated with the blocking of antigen-dependent B-cell receptor (Bcr) signaling rather than inhibition of constitutive Syk activity. R935788 treatment at 80 mg/kg/day for 18-21 days potently inhibits tumor growth of TCL1-002, TCL1-551 and TCL1-870 in mice with undetectable leukemic CD5+/B220+ cells at the last day of treatment, significantly prolongs the survival of the treated mice with median survival increased from 45/46 days to 170/172 days, and completely eradicates the malignant cells in a substantial proportion of mice after a 6-month follow-up period without affecting the production of normal B lymphocytes. R935788 treatment also induces an early and transient migration of both normal and malignant B cells from spleen and lymph nodes to peripheral blood, which is subsequently followed by selective growth inhibition of the malignant B-cell population. In addition, R935788 is also effective against spontaneously developing TCL1 leukemias in Eμ-TCL1 transgenic mice. [3]

Protocol

Kinase Assay:

[1]
+ Expand

In vitro fluorescence polarization kinase assays:

R406 (in vitro active form of R935788) is serially diluted in DMSO and then diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg/mL acetylated BGG). ATP and substrate in kinase buffer are added at room temperature, resulting in a final DMSO concentration on 0.2%. The kinase reactions are performed in a final volume of 20 μL containing 5 μM HS1 peptide substrate and 4 μM ATP and started by addition of 0.125 ng of Syk in kinase buffer. The reaction is allowed to proceed for 40 minutes at room temperature. The reaction is stopped by the addition of 20 μL of PTK quench mix containing EDTA/anti-phosphotyrosine antibody (1× final)/fluorescent phosphopeptide tracer (0.5× final) diluted in FP Dilution Buffer. The plate is incubated for 30 minutes in the dark at room temperature and then read on a Polarion fluorescence polarization plate reader. Data is converted to determine the amount of phosphopeptide present using a calibration curve generated by competition with the phosphopeptide competitor provided in the Tyrosine Kinase Assay Kit. For IC50 determination, R406 is tested at eleven concentrations in duplicate and curve-fitting is performed by non-linear regression analysis using Prism GraphPad Software.
Cell Research:

[2]
+ Expand
  • Cell lines: TCL1-002, TCL1-252, TCL1-551, TCL1-870, and TCL1-540
  • Concentrations: Dissolved in DMSO, final concentrations ~10 μM
  • Incubation Time: 48 hours
  • Method:

    Cells are exposed to increasing concentrations of R406 (in vitro active form of R935788) for 48 hours. The percentage of apoptotic cells is determined by double staining with propidium iodide (PI) and annexin-A5–FITC conjugate. Ki-67 staining is performed with the FITC mouse anti–Ki-67 set. Samples are analyzed on a FACSCalibur flow cytometer with CellQuest Version 3.3 software.


    (Only for Reference)
Animal Research:

[2]
+ Expand
  • Animal Models: B6/C3H F1 female mice intraperitoneally injected with TCL1-002, TCL1-551, or TCL1-870 leukemia cells, and Eμ-TCL1 transgenic mice
  • Formulation: Formulated as a 4 mg/mL solution in 0.1% carboxymethylcellulose sodium, 0.1% methylparaben, and 0.02% propylparaben (pH 6.5)
  • Dosages: 80 mg/kg/day
  • Administration: Intraperitoneal administration in 3 divided doses at 3-hour intervals
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 6 mg/mL warmed (9.6 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
0.5% CMC+0.25% Tween 80,pH6.5
For best results, use promptly after mixing. 		30 mg/mL

* 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 Information

Molecular Weight 624.42
Formula

C23H24FN6O9P.2Na
CAS No. 1025687-58-4
Storage powder
in solvent
Synonyms Tamatinib Fosdium

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02611063 Recruiting Drug: fostamatinib Hematological Malignancies Stefanie Sarantopoulos MD PhD.|Duke University January 2016 Phase 1
NCT01725230 Completed Drug: Fostamatinib|Drug: Rosuvastatin|Drug: Simvastatin Rheumatoid Arthritis AstraZeneca November 2012 Phase 1
NCT01608542 Completed Drug: Fostamatinib 100mg|Drug: Fostamatinib 200mg Healthy Japanese Volunteers AstraZeneca June 2012 Phase 1
NCT01598571 Completed Drug: Fostamatinib Healthy AstraZeneca May 2012 Phase 1
NCT01569074 Terminated Drug: Fostamatinib|Drug: Placebo Rheumatoid Arthritis AstraZeneca April 2012 Phase 2

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

  • Question 1:

    What’s the difference between S2625 and S2206?

  • Answer:

    The differences between S2625 and S2206: 1. S2206 is more stable than S2625; 2. The water solubility of S2206 is better than S2625; 3. The absorption of S2206 is harder than S2625, so you need to test the suitable dosage if you use the product in animal assays; 4. The potency of S2206 and S2625 is similar.

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Syk Signaling Pathway Map

Syk Inhibitors with Unique Features

  • Most Potent Syk Inhibitor

    PRT062607 (P505-15, BIIB057) HCl : Syk, IC50=1 nM.

  • Syk Inhibitor in Clinical Trial

    Fostamatinib (R788) : Phase III for Rheumatoid Arthritis.

  • Newest Syk Inhibitor

    PRT062607 (P505-15, BIIB057) HCl : Novel, highly selective Syk inhibitor with IC50 of 1 nM, >80-fold selective for Syk than Fgr, Lyn, FAK, Pyk2 and Zap70.

  • Classic Syk Inhibitor

    R406 : Syk inhibitor with IC50 of 41 nM, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. Phase 2.

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  • SU6656 New

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  • R406 (free base)

    R406 (free base) is a potent Syk inhibitor with IC50 of 41 nM in a cell-free assay, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. Phase 1.

  • R406

    R406 is a potent Syk inhibitor with IC50 of 41 nM in cell-free assays, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. Phase 1.

    Features:Lead drug candidate for rheumatoid arthritis.

  • Fostamatinib (R788)

    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.

    Features:Converted into its active metabolite R406 in vivo.

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  • PRT062607 (P505-15, BIIB057) HCl

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID