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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  • 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.

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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 NXvGSIdES3m2b4TvfIlkyqCjc4PhfS=> NFPYOYpEgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckBT[W2xczDj[YxteyxiSVO1NF0xNjJ4NzFOwG0> NI\UcYMzOzF3MUC1OC=>

... Click to View More Cell Line Experimental Data

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]

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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 individually and in order:
0.5% CMC+0.25% Tween 80,pH6.5
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
Synonyms Tamatinib Fosdium

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Clinical Trial Information

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 Completed Immune Thrombocytopenic Purpura Rigel Pharmaceuticals November 2014 Phase 3
NCT02112838 Recruiting IGA Nephropathy Rigel Pharmaceuticals October 2014 Phase 2
NCT02077192 Recruiting Immune Thrombocytopenic Purpura Rigel Pharmaceuticals July 2014 Phase 3

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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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID