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抑制剂描述:

产品名称:Fostamatinib

产品别名:见爱必信官网

英文别名:Fostamatinib

靶点:Syk

CAS:901119-35-5

纯度:>98%

外观:见爱必信官网

保存方法:Store at -20℃ for one year(Powder);Store at 2-4℃ for two weeks;Store at -20℃ for six months after dissolution.

描述:

Fostamatinib (R788)是活性代谢产物R406的前体药物,是一种Syk抑制剂,IC50为41 nM,强效抑制Syk但不抑制Lyn,对Flt3作用效果低5倍。R935788是R406亚甲基磷酸言药物前体,可在体内快速转化为R406。R406(R935788的活性形式)选择性抑制Syk依赖性信号,EC50为33 nM 到171 nM,比作用于Syk非依赖性通路更有效。R406抑制多种弥散性大B细胞淋巴瘤(DLBCL)细胞系增殖,EC50为 0.8 μM到8.1 μM。R406 处理,降低BLNK, Akt, GSK-3, FOXO和ERK 磷酸化。此外, R406作用于TCL1白血病,完全抑制抗-IgM抗体诱导的BCR信号。尽管TCL1白血病中存在高水平的组成型激活的Syk,但是R406对白血病细胞没有选择毒性。

溶解性:DMSO :107 mg/mL (184.3 mM)

体外研究:

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 Fc?RI 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 ).

体内研究: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.

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