General
Preferred name
FOSTAMATINIB
Synonyms
R-935788 Sodium ()
R-788 Sodium ()
FOSTAMATINIB DISODIUM ()
R-788, R-935788, R-788 Sodium, R-788 Free acid, R-935788 Sodium, R-935788 Free acid, Fostamatinib Disodium ()
R788 ()
R788(Disodium) ()
R788 (Fostamatinib) Disodium ()
Tamatinib Fosdium ()
R788 Disodium ()
R788(Disodium)R788 (Fostamatinib) Disodium ()
R935788 ()
R788 (Fostamatinib) ()
R-788 ()
R-788 FREE ACID ()
R-935788 ()
R-935788 FREE ACID ()
R788 FREE ACID ()
R935788 FREE ACID ()
Fostamatinib (R788) ()
Fostamatinib (R788) disodium ()
Fostamatinib sodium ()
R788 (sodium salt) ()
P&D ID
PD010914
CAS
901119-35-5
1025687-58-4
Tags
available
drug candidate
prodrug
drug
Approved by
PMDA
EMA
FDA
First approval
2018
Drug Status
investigational
approved
Drug indication
Thrombocytopenia
Rheumatoid arthritis
Immune thrombocytopenic purpura
Max Phase
Phase 4
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
DESCRIPTION
Fostamatinib was an investigational spleen tyrosine kinase (Syk) inhibitor, although development in rheumatoid arthritis was discontinued in 2013 due to a lack of observed efficacy. The compound is administered orally as a disodium salt (PubChem CID 25008120) and this prodrug is rapidly converted to by alkaline phosphatases in intestinal enterocytes .
PHARMACODYNAMICS
The active metabolite of fostamatinib, R406, inhibits signal transduction by Fcγ receptors involved in the antibody-mediated destruction of platelets by immune cells in chronic ITP [A32898,A32899,FDA Label]. This results in increased platelet counts in this population.; ; R406 produces inhibition of T and B lymphocyte activation by T-cell receptors (TCRs) and B-cell receptors (BCRs) respectively [A32898,A32899]. It can also inhibit signalling via Fcε receptors which could have applications in treating allergic symptoms through prevention of mast cell degranulation [A32899,A32903]. Inhibition of Fc receptor signalling system also affected by R406 suppresses both dendritic cell maturation and antigen presentation and may contribute to the effects of fostamatinib [A32904]. As a knock-on effect of disabling signal transduction from Fc receptors, TCRs, and BCRs, the production of inflammatory mediators and cytokines like tumour necrosis factor α, leukotriene C4, interleukin-8, and granulocyte-macrophage colony-stimulating factor.; ; Fostamatinib can produce hypertension through off-target effects [A32906,FDA Label];
TOXICITY
Neither fostamatinib or R406 were found to be carcinogenic or mutagenic [FDA Label]. Fostamatinib can cause embryo-fetal mortality or developmental abnormalities at exposures of 0.3-10 times the maximum recommended human dose.; ; Serious adverse effects include hypertension, neutropenia, diarrhea, and hepatotoxicity [FDA Label]
ABSORPTION
Fostmatinib is the methylene phosphate prodrug of R406, the active metabolite [FDA Label]. It is extensively hydrolyzed by intestinal alkaline phosphatase. Only negligible amounts of fostamatinib enter systemic circulation [A32934,FDA Label].; ; R406 has an absolute bioavailability of 55% and reaches peak plasma concentrations in approximately 1.5 h [A32934,FDA Label]. Administration with a high calorie, high fat meal increases exposure by 23% and the maximum plasma concentration by 15%. This may lengthen time to peak plasma concentration to approximately 3 h [A32934]. Exposure to R406 is known to be dose proportional up to 200 mg twice daily [FDA Label]. R406 accumulates 2-3 fold with twice daily dosing at 100-160 mg.
DESCRIPTION
Fostamatinib was an investigational spleen tyrosine kinase (Syk) inhibitor prodrug. Although development in rheumatoid arthritis was discontinued in 2013 due to a lack of observed efficacy, development is ongoing for chronic and persistent immune thrombocytopenia (ITP). Fostamatinib is administered orally as a disodium salt (PubChem CID 25008120). It is rapidly converted to by alkaline phosphatases in intestinal enterocytes .
MOA
The active metabolite of fostamatinib, R406, is an inhibitor of spleen tyrosine kinase (Syk) [A32899]. It binds reversibly to the ATP binding pocket with high affinity (Ki = 30nM), inhibiting the kinase activity with an IC50 of 41nM.; ; Syk is a cytosolic protein kinase and part of the signalling cascade which occurs with Fc receptors, TCRs, and BCRs [A32898]. It contains two src homology 2 (SH2) domains separated by a linker domain. These SH2 domains bind to tyrosine residues on the immunoreceptor tyrosine-based activating motif phosphorylated by Lyn, another kinase in the cascade. This motif is located on the cytoplasmic regions of several immune receptors including Fc receptors, TCRs, BCRs, and natural killer cell receptors. The flexibility provided by the linker enables the protein to bind to many receptor types. Inhibition of Syk suppresses downstream signal transduction [A32899].; ; While Syk plays a role in some pathways involved in the generation of the oxidative burst by neutrophils or phagocytosis by macrophages, R406 does not have a significant effect on these processes [A32899]. This is likely due to redundant pathways which do not involve Syk. Similarly Syk does not produce significant effects on platelet activation despite its involvement in glycoprotein IV and integrin based signalling. Activation of antibody-dependent cell-mediated toxicity by natural killer cells is also unaffected despite the involvement of Syk in Fc receptor signalling [A32898].; ; R406 binds to the adenosine A3 receptor as an antagonist as well as the adenosine and monoamine uptake transporters as an inhibitor [A32899,A32906]. It has also been found to be an inhibitor of UDP glucuronosyltransferase UGT1A1, phosphodiesterase PDE5, fatty acid amide hydrolase, 5-lipoxygenase, cathepsin L, and cathepsin S [A32906]. R406 appears to inhibit a wide range of kinases at higher concentrations [A32906]. It is thought that inhibition of some of these targets may be responsible for the increase in blood pressure seen with fostamatinib.; ;
DESCRIPTION
Fostamatinib is a spleen tyrosine kinase (Syk) inhibitor prodrug. Fostamatinib is administered orally in disodium salt preparations (e.g. PubChem CID 25008120 and fostamatinib disodium hexahydrate CID 24828759). It is rapidly converted to by alkaline phosphatases in intestinal enterocytes . Although development in rheumatoid arthritis was discontinued in 2013 due to a lack of observed efficacy, development continued in patients with chronic and persistent immune thrombocytopenia (ITP).
(GtoPdb)
DESCRIPTION
Indicated for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who have had an insufficient response to a previous treatment
(PKIDB)
DESCRIPTION
R788 (Fostamatinib) disodium, 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.
(BOC Sciences Bioactive Compounds)
DESCRIPTION
Fostamatinib, a prodrug of the active metabolite R406, is a Syk inhibitor with IC50 of 41 nM, strongly inhibiting Syk but not Lyn, and 5-fold less potent to Flt3.
(BOC Sciences Bioactive Compounds)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Compound Sets
22
BOC Sciences Bioactive Compounds
Cayman Chemical Bioactives
ChEMBL Approved Drugs
ChEMBL Drugs
Clinical kinase drugs
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP Approved Drugs
Guide to Pharmacology
LSP-MoA library (Laboratory of Systems Pharmacology)
LSP-OptimalKinase library (Laboratory of Systems Pharmacology)
NCATS Inxight Approved Drugs
PKIDB
ReFrame library
Selleckchem Bioactive Compound Library
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
53
Molecular Weight
580.15
Hydrogen Bond Acceptors
12
Hydrogen Bond Donors
4
Rotatable Bonds
10
Ring Count
4
Aromatic Ring Count
3
cLogP
3.09
TPSA
186.72
Fraction CSP3
0.3
Chiral centers
0.0
Largest ring
6.0
QED
0.26
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Targets
SYK
Pathway
Angiogenesis
GPCR/G protein
Membrane Transporter/Ion Channel
Neuroscience
Tyrosine Kinase/Adaptors
Protein Tyrosine Kinase/RTK
Target
Adenosine transporter
A3
Monoamine transporter
FLT3
Indication
chronic immune thrombocytopenia (ITP)
MOA
Syk inhibitor
Source data
