Fostamatinib (R788) serves as the oral prodrug of the active compound R406 [1]. R406, an orally active and competitive inhibitor of Syk/FLT3, possesses a Ki of 30 nM and an IC50 of 41 nM[2]. R406 additionally demonstrates inhibition of Lyn (IC50=63 nM) and Lck (IC50=37 nM) [3].
体内研究
Fostamatinib (R788) exhibits high bioavailability and rapid absorption in Louvain rats. Following a single oral dose of R788 at 10 mg/kg or 20 mg/kg, R406 shows the following pharmacokinetic parameters: AUC0-16 hrs=10618 ngh/mL and 30650 ngh/mL respectively; Cmax=2600 ng/mL and 6500 ng/mL respectively (observed at 1 hour); t1/2=4.2 hours. The prodrug was not detected in plasma, indicating complete conversion of R788 to R406 [1].
Fostamatinib/福他替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Kidney tubular epithelial cell line (P cells)
200 nM
48 h
To evaluate the effect of R406 (active metabolite of Fostamatinib) on MUC1 protein levels; results showed R406 significantly reduced MUC1 abundance on the plasma membrane and increased its intracellular distribution
Cell Rep Med. 2020 Oct 29;1(8):100137.
MWCL.1 cells
1 μM
3 days
To evaluate the effect of Fostamatinib on the viability of MWCL-1 cells, results showed that 1 μM Fostamatinib significantly reduced cell viability after 3 days, inducing cell cycle arrest and apoptosis.
Clin Cancer Res. 2015 Jun 1;21(11):2538-45.
BCWM.1 cells
1 μM
3 days
To evaluate the effect of Fostamatinib on the viability of BCWM.1 cells, results showed that 1 μM Fostamatinib significantly reduced cell viability after 3 days, inducing cell cycle arrest and apoptosis.
Clin Cancer Res. 2015 Jun 1;21(11):2538-45.
EBV+ B-cell lymphoma PTLD lines
0-10 μM
96 h
Induces apoptosis and cell cycle arrest while decreasing downstream PI3K/Akt signaling
Am J Transplant. 2013 Apr;13(4):883-890.
Bone marrow monocytes
10 ng/ml GM-CSF and 10 ng/ml IL-3
5 days
To evaluate the effect of Fostamatinib on GM-CSF/IL-3 stimulated bone marrow monocyte colony formation, results showed that Fostamatinib reduced GM-CSF/IL-3 stimulated bone marrow monocyte colony formation.
Basic Res Cardiol. 2016 Mar;111(2):20.
Ly6Chigh monocytes
30 ng/ml M-CSF
16 h
To evaluate the effect of Fostamatinib on monocyte to macrophage differentiation, results showed that Fostamatinib blocked M-CSF stimulated monocyte to macrophage differentiation.
Basic Res Cardiol. 2016 Mar;111(2):20.
Fostamatinib/福他替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
Ischemia/reperfusion (I/R)-induced acute lung injury model
Oral
3 g/kg
Once daily for 10 days
To evaluate the effect of R788 on MUC1 levels in vivo; results showed R788 significantly reduced MUC1 abundance in lung epithelial cells
Cell Rep Med. 2020 Oct 29;1(8):100137.
Mice
Silicosis mouse model
Oral gavage
80 mg/kg
Once daily for two weeks
To investigate the effect of Fostamatinib on p-SYK levels and pulmonary fibrosis in a silicosis mouse model. Results showed that Fostamatinib significantly inhibited p-SYK levels and effectively alleviated silica-induced alveolitis and pulmonary fibrosis.
Signal Transduct Target Ther. 2022 May 13;7(1):157
Non-obese diabetic mice
MWCL-1 cell xenograft model
Intraperitoneal injection
80 mg/kg
Three times a week for 45 days
To evaluate the anti-tumor activity of Fostamatinib in the MWCL-1 cell xenograft model, results showed that Fostamatinib significantly slowed tumor growth.
Clin Cancer Res. 2015 Jun 1;21(11):2538-45.
Mice
Apoe-/- mice on high cholesterol diet
Oral
0.3% (w/w)
Continued for 8 weeks
To evaluate the effect of Fostamatinib on high cholesterol diet-induced atherosclerosis, results showed that Fostamatinib reduced the formation of atherosclerotic plaques and decreased the number of Ly6Chigh monocytes and macrophages.
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