Fostamatinib (R788)

ArtNr	S2625-5000
Hersteller	Selleckchem
CAS-Nr.	901119-35-5
Menge	5 g
Quantity options	10 mg 100 mg 1 g 10 g 10 mM/1 mL 2 mg 5 mg 50 mg 5 g
Kategorie	Oncology Neuroscience Neuroinflammation Metabolism Diabetes Glucose Homeostasis Inhibitors & Compound Libraries Small Molecules By Organ Colorectal Cancer Heart & Blood Cancer
Typ	Inhibitors
Specific against	other
Smiles	CC1(C(=O)N(C2=C(O1)C=CC(=N2)NC3=NC(=NC=C3F)NC4=CC(=C(C(=C4)OC)OC)OC)COP(=O)(O)O)C
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	901119-35-5'
Similar products	R788
Lieferbar
Manufacturer - Targets	SYK
Storage Conditions	2 years -80 in solvent
Molecular Weight	580, 46
Administration	Orally b.i.d
Animal Models	Balb/c mice with arthritis
Cell lines	Cultured human mast cells (CHMC)
Clinical Trials	R788 has entered in a phase III clinical trial in the treatment of rheumatoid arthritis.
Concentrations	0 uM -100 uM
Dosages	1 mg/kg or 5 mg/kg
Formulation	35% TPGS, 60% PEG 400, 5% propylene glycol
IC50	41 nM, 41 nM, 41 nM, 41 nM, 41 nM, 41 nM
In vitro	R788 is a prodrug of the spleen tyrosine kinase (Syk) inhibitor R-406. R406 is a competitive inhibitor for ATP binding with a Ki of 30 nM. R406 dose-dependently inhibits anti-IgE-mediated CHMC degranulation with an EC50 of 56 nM. R406 also inhibits the anti-IgE-induced production and release of LTC4 and cytokines and chemokines, including TNFalpha, IL-8, and GM-CSF. Inhibition of Syk by R406 results in inhibition of all phosphorylation events downstream of Syk signaling. Next to FcepsilonRI signaling in CHMC, R406 most potently inhibits the signaling of IL-4 and IL-2 receptors. R406 specifically inhibits FcgammaR signaling in human mast cells, macrophages, and neutrophils. R406 can inhibit local inflammatory injury mediated by immune complexes. [1] R406 induces apoptosis of the majority of examined DLBCL cell lines. In R406-sensitive DLBCL cell lines, R406 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 R406 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]
Incubation Time	30 minutes
Kinase Assay	Fluorescence polarization kinase assay and Ki determination, The fluorescence polarization reactions are performed. For Ki determination, duplicate 200-uL reactions are set up at eight different ATP concentrations from 200 uM (2-fold serial dilutions) in the presence of either DMSO or R406 at 125, 62.5, 31.25, 15.5, or 7.8 nM. At different time points, 20 uL of each reaction is removed and quenched to stop the reaction. For each concentration of R406, 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.
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 R406 or DMSO for 30 minutes. Cells are then stimulated with either 0.25 to 2 mg/mL anti-IgE or anti-IgG or 2 uM 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.
Solubility (25C)	DMSO 116 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Information	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.
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
Features	Converted into its active metabolite R406 in vivo.

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