Fostamatinib (R788) is the oral prodrug of the active compound R406, a relatively selective small molecule inhibitor of Syk [1]. R406 is a competitive inhibitor for ATP binding to the Syk catalytic domain (Ki = 30 nM), and inhibits Syk kinase activity in vitro with an IC50 of 41 nM [2].
Fostamatinib (R788) induced a time- and dose-dependent reduction in viability of Waldenstr?m macroglobulinemia (WM) MWCL-1 and BWCM.1 cells, with IC50 that were in the physiologically relevant range of approximately 0.25 and 1 μM, respectively, at 3 days [3]. Fostamatinib (R788) greatly inhibited the proliferation of six HPV-negative HNSCC cell lines in vitro [4].
Fostamatinib (R788) (80 mg/kg/d, 21d) significantly prolonged the survival of mice challenged with the leukemia lines TCL1-551 and TCL1-870 [5]. Fostamatinib (R788)(80 mg/kg/d, 7d) has shown efficacy in murine models of non-Hodgkin`s lymphoma (NHL), reducing tumour burden and prolonging survival in treated mice [6]. A single oral dose of R788 10 mg/kg or 20 mg/kg: Cmax = 2600 ng/ml and 6500 ng/ml respectively (observed at 1 hour), t1/2 = 4.2 hours in Louvain rats [7].
References:
[1]. McAdoo S P, Tam F W K. Fostamatinib disodium[J]. Drugs of the Future, 2011, 36(4): 273.
[2]. Braselmann S, Taylor V, Zhao H, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation[J]. Journal of Pharmacology and Experimental Therapeutics, 2006, 319(3): 998-1008.
[3]. Kuiatse I, Thomas S K, Weber D M, et al. Inhibition of spleen tyrosine kinase with fostamatinib shows pre-clinical activity against models of Waldenstr?m macroglobulinemia[J]. Blood, 2012, 120(21): 3723.
[4]. Tian G, Fu Y, Zhang D, et al. Identification of four key prognostic genes and three potential drugs in human papillomavirus negative head and neck squamous cell carcinoma[J]. Cancer cell international, 2021, 21(1): 1-18.
[5]. Suljagic M, Longo P G, Bennardo S, et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ-TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling[J]. Blood, The Journal of the American Society of Hematology, 2010, 116(23): 4894-4905.
[6]. Young R M, Hardy I R, Clarke R L, et al. Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target[J]. Blood, The Journal of the American Society of Hematology, 2009, 113(11): 2508-2516.
[7]. Pine P R, Chang B, Schoettler N, et al. Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor[J]. Clinical immunology, 2007, 124(3): 244-257.
Fostamatinib (R788) 是活性化合物 R406 的口服前药，R406 是一种相对选择性的 Syk 小分子抑制剂[1]。 R406 是 ATP 结合 Syk 催化结构域 (Ki = 30 nM) 的竞争性抑制剂，在体外抑制 Syk 激酶活性，IC50 为 41 nM [2]。
Fostamatinib (R788) 诱导 WaldenstrÖm 巨球蛋白血症 (WM) MWCL-1 和 BWCM.1 细胞的存活时间和剂量依赖性降低，IC50 分别在大约 0.25 和 1 μM 的生理相关范围内，第 3 天 [3]。 Fostamatinib (R788) 在体外显着抑制了 6 种 HPV 阴性 HNSCC 细胞系的增殖[4]。
Fostamatinib (R788)（80 mg/kg/d，21 天）显着延长了受到白血病细胞系 TCL1-551 和 TCL1-870 攻击的小鼠的存活时间 [5]。 Fostamatinib (R788)（80 mg/kg/d，7 天）在非霍奇金淋巴瘤 (NHL) 小鼠模型中显示出疗效，可减轻治疗小鼠的肿瘤负荷并延长生存期[6] .单次口服 R788 10 mg/kg 或 20 mg/kg:Louvain 大鼠的 Cmax = 2600 ng/ml 和 6500 ng/ml（1 小时观察），t1/2 = 4.2 小时 [7] .