R788 (Fostamatinib) Disodium

Name: R788 (Fostamatinib) Disodium
Brand: Selleck Chemicals
SKU: S2206
Rating: 5 (4 reviews)

For research use only. Not for use in humans.

Catalog No.S2206 Synonyms: Tamatinib Fosdium

4 publications

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.

Selleck's R788 (Fostamatinib) Disodium has been cited by 4 publications

Pharmacol Res, 2018, 128:244-251.

PubMed: 29079427 ( click the link to review the publication )

Oncotarget, 2017, 8(67):111495-111507

PubMed: 29340070 ( click the link to review the publication )

Cytokine, 2016, 90:73-79

PubMed: 27816795 ( click the link to review the publication )

Clin Cancer Res, 2015, 21(11):2538-45

PubMed: 25748087 ( click the link to review the publication )

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

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	NWC0UlQ3S3m2b4TvfIlkyqCjc4PhfS=>				MoXqR5l1d3SxeHnjbZR6KGGpYXnud5QhcHWvYX6gVoFud3NiY3XscJMtKEmFNUC9NE4zPjdizszN	MV[yN\|E2OTB3NB?=

... 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 Oncotarget 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 Clin Cancer Res 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 Clin Cancer Res 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 Clin Cancer Res 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]	- Collapse 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]	- Collapse 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]	- Collapse 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)

References

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 Download R788 (Fostamatinib) Disodium SDF

Molecular Weight	624.42
Formula	C₂₃H₂₄FN₆O₉P.2Na
CAS No.	1025687-58-4
Storage	3 years -20°C powder
Storage	2 years -80°C in solvent
Synonyms	Tamatinib Fosdium
Smiles	[Na+].[Na+].COC1=C(OC)C(=CC(=C1)NC2=NC=C(F)C(=N2)NC3=CC=C4OC(C)(C)C(=O)N(CO[P]([O-])([O-])=O)C4=N3)OC

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Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2019-10-14)

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

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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.

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.

Related Syk Products

PX-478 2HCl ^New

PX-478 2HCl is an orally active, and selective hypoxia-inducible factor-1α (HIF-1α) inhibitor. Phase 1.
Defactinib (VS-6063) ^New

Defactinib (VS-6063, PF-04554878) is a selective, and orally active FAK inhibitor. Phase 2.
SU6656 ^New

SU 6656 is a selective Src family kinase inhibitor with IC50 of 280 nM, 20 nM, 130 nM, and 170 nM for Src, Yes, Lyn, and Fyn, respectively.
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.
Piceatannol

Piceatannol, a natural stilbene, is a selective Syk inhibitor and ~10-fold selectivity versus Lyn.
PRT062607 (P505-15) HCl

PRT062607 (P505-15, BIIB057) HCl is a novel, highly selective Syk inhibitor with IC50 of 1 nM in cell-free assays, >80-fold selective for Syk than Fgr, Lyn, FAK, Pyk2 and Zap70.
Entospletinib (GS-9973)

Entospletinib (GS-9973) is an orally bioavailable, selective Syk inhibitor with IC50 of 7.7 nM in a cell-free assay and showed 13- to >1000-fold cellular selectivity for Syk over other kinases(including Jak2, ckit, Flt3, Ret, KDR) as assessed by target protein phosphorylation or functional response.
Ibrutinib (PCI-32765)

Ibrutinib (PCI-32765) is a potent and highly selective Brutons tyrosine kinase (Btk) inhibitor with IC50 of 0.5 nM in cell-free assays, modestly potent to Bmx, CSK, FGR, BRK, HCK, less potent to EGFR, Yes, ErbB2, JAK3, etc.

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R788 (Fostamatinib) Disodium