R406 is a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling. R406 inhibits the anti-IgE-induced production and release of LTC4 and cytokines and chemokines, including TNFα, IL-8, and GM-CSF. R406 inhibits phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 binds to the ATP binding pocket of Syk and inhibits its kinase activity as an ATP-competitive inhibitor with K of 30 nM. R406 blocks Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and Bcr-mediated activation of B lymphocytes. R406 significantly induces chronic lymphocytic leukemia (CLL) cell apoptosis in nurselike cells cocultures and blocks CCL3 and CCL4 secretion by CLL cells in response to B-cell antigen receptor (Bcr) triggering. R406 is a potent inhibitor of platelet signaling and functions initiated by FcγRIIA cross-linking by specific antibodies or by sera from HIT patients.
R406 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Kidney tubular epithelial cell line (P cells)
200 nM
48 hours
To evaluate the effect of R406 (active metabolite of Fostamatinib) on MUC1 protein levels. Results showed that R406 significantly reduced MUC1 abundance on the plasma membrane and increased its intracellular distribution.
Cell Rep Med. 2020 Oct 29;1(8):100137.
Ly6Chigh monocytes
1 μM R406
16 hours
Evaluate the effect of R406 on M-CSF stimulated monocyte to macrophage differentiation. Results showed R406 blocked the differentiation process.
Basic Res Cardiol. 2016 Mar;111(2):20.
Bone marrow cells
0.1 μM and 1 μM R406
5 days
Evaluate the effect of R406 on GM-CSF/IL-3 stimulated colony formation of bone marrow cells. Results showed R406 significantly reduced colony formation.
Basic Res Cardiol. 2016 Mar;111(2):20.
Spleen B-cells from TCL1 Tg mice
2.5 μM
48 h
Suppression of Foxm1 and Ccl3 expression, indicating that R406 regulates Foxm1 and Ccl3 expression through inhibition of BCR signaling
Leukemia. 2015 Jun;29(6):1350-9.
Chronic Lymphocytic Leukemia cells
100 μM
1 h
R406, as a SYK inhibitor, was used to study its effects on Chronic Lymphocytic Leukemia cells. The results showed that R406 could block the anti-apoptotic effects of LAG3-Fc on CLL cells.
Haematologica. 2017 May;102(5):874-882.
B1-8 B cells
5 μM
60 min
To study the effect of Syk inhibitor R406 on B cell activation, results showed that R406 completely blocked the dissociation of BCR oligomers.
Enhanced cytotoxicity when combined with paclitaxel
Cancer Cell. 2015 Jul 13;28(1):82-96.
microglia
1 mM
24 h
Inhibit SYK kinase, reduce inflammatory response
Cell Death Dis. 2019 Jul 19;10(8):555.
U87
10 μM
48 h
R406 had minimal inhibitory effect on U87 cells, with an IC50 greater than 1 mM.
Cell Death Dis. 2019 May 1;10(5):358.
C17.2
10 μM
48 h
R406 was non-toxic to C17.2 cells, even at a concentration of 10 μM.
Cell Death Dis. 2019 May 1;10(5):358.
U251
10 μM
48 h
R406 had minimal inhibitory effect on U251 cells, with an IC50 greater than 1 mM.
Cell Death Dis. 2019 May 1;10(5):358.
GSC-1
1 μM
48 h
R406 significantly inhibited the proliferation of GSC-1 cells, with an IC50 of 0.75 μM.
Cell Death Dis. 2019 May 1;10(5):358.
GSC-2
1 μM
48 h
R406 significantly inhibited the proliferation of GSC-2 cells, with an IC50 of 0.89 μM.
Cell Death Dis. 2019 May 1;10(5):358.
Monocytes
2 mM
24 h
To investigate the effects of R406 on red blood cell phagocytosis and TNF-α production. The results showed that R406 significantly reduced red blood cell phagocytosis and TNF-α production
Haematologica. 2024 Feb 1;109(2):444-457.
R406 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
K14-HPV16 transgenic mice
Oral
2.0 g/kg/day
Starting at 1 month of age, continuing to 4 months of age
In K14-HPV16 mice, fostamatinib (R788) inhibited Syk kinase activity and effectively blocked progression from low-grade hyperplasia to high-grade dysplasia.
Cancer Cell. 2014 Jun 16;25(6):809-821
C57BL/6J mice
MPTP-induced Parkinson's disease model
Intraperitoneal injection
5 mg/kg
Once daily for 5 consecutive days
Inhibition of SYK activity to alleviate neuroinflammation
Neural Regen Res. 2024 Jun 1;19(6):1375-1384.
Nude mice
SKOV3c.2 subcutaneous tumor model
Intraperitoneal injection
6.5 mg/kg
Every three days, multiple cycles
Significantly reduced tumor weight when combined with paclitaxel
Cancer Cell. 2015 Jul 13;28(1):82-96.
C57BL/6J mice
Middle cerebral artery occlusion model
Intraperitoneal injection
5 mg/kg
Once daily for 3 consecutive days
Inhibit SYK kinase, reduce inflammatory response and neuronal injury
Cell Death Dis. 2019 Jul 19;10(8):555.
BALB/c-nu/nu mice
Subcutaneous tumor model
Intraperitoneal injection
20 mg/kg
Daily, continuous treatment
R406 significantly inhibited tumor growth initiated by GSC-1 cells, and the combination with TMZ showed enhanced efficacy.
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