Home Angiogenesis Syk inhibitor Fostamatinib disodium hexahydrate

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Fostamatinib disodium hexahydrate Syk inhibitor

Cat.No.S4944

Fostamatinib (R788) disodium (Tamatinib Fosdium) hexahydrate, a prodrug of the active metabolite R406, is a Syk inhibitor with IC50 of 41 nM in a cell-free assay.
Fostamatinib disodium hexahydrate Syk inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 732.51

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Quality Control

Batch: S494401 DMSO]100 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false Purity: 99.8%
99.8

Solubility

In vitro
Batch:

DMSO : 100 mg/mL (136.51 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 732.51 Formula

C23H36FN6Na2O15P

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 914295-16-2 -- Storage of Stock Solutions

Synonyms Tavalisse, R788 disodium hexahydrate, Tamatinib Fosdium hexahydrate Smiles O.O.O.O.O.O.[Na+].[Na+].COC1=CC(=CC(=C1OC)OC)NC2=NC=C(F)C(=N2)NC3=NC4=C(OC(C)(C)C(=O)N4CO[P]([O-])([O-])=O)C=C3

Mechanism of Action

Targets/IC50/Ki
Syk
(Cell-free assay)
41 nM
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. 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]).
Kinase Assay
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. Finally the apparent Km (or apparent Ki/Vmax) is plotted against the inhibitor concentration to determine the Ki.
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. 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. 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.
References
  • [4] https://pubmed.ncbi.nlm.nih.gov/19333898/
  • [5] https://pubmed.ncbi.nlm.nih.gov/16946104/

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT05904093 Not yet recruiting
Sickle Cell Disease|Hb-SS Disease|Hemoglobin S|Disease Sickle Cell Anemia|Sickle Cell Disorders|Hemoglobin Beta Thalassemia Disease
National Heart Lung and Blood Institute (NHLBI)|National Institutes of Health Clinical Center (CC)
 May 15 2024 Phase 1
NCT05509582 Enrolling by invitation
Immune Mediated Anemia|Immune Mediated Thrombocytopenia|Chronic GVHD
National Heart Lung and Blood Institute (NHLBI)|National Institutes of Health Clinical Center (CC)
 May 15 2024 Phase 2
NCT06071520 Completed
Primary Immune Thrombocytopenia
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
 March 1 2023 --
NCT05613296 Not yet recruiting
ITP - Immune Thrombocytopenia|Chronic ITP|Refractory ITP
Gruppo Italiano Malattie EMatologiche dell''Adulto
 February 2023 --
NCT04543279 Terminated
Myelofibrosis|Thrombocytopenia
Washington University School of Medicine|Rigel Pharmaceuticals
 May 3 2021 Phase 2
NCT04904276 Terminated
ITP|Immune Thrombocytopenia
Rigel Pharmaceuticals
 May 18 2021 --

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