Fostamatinib (R788)|901119-35-5|安捷凯

Background

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].

参考文献:
[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 Waldenstr?m 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].

Protocol

Cell experiment [1]:

Cell lines

Head and neck squamous cell carcinoma (HNSCC) HN4, HN6, HN30, SCC9, SCC25 and CAL27 cell lines

Preparation Method

Approximately 3 × 10³ cells per well were seeded in 96-well culture plates. After culture for 24 h, the medium was removed. Fostamatinib (R788) at different concentrations were added with the volume of 100 μl. For the negative control wells, drug-free medium was added and cultured for 72 h.

Reaction Conditions

0-10⁶ nM for 72 hours

Applications

The proliferation of all cell lines was inhibited by Fostamatinib, The IC50 values of fostamatinib was range from 0.811 to 3.470 μM.

Animal experiment [2]:

Animal models

Female NZB/NZW mice

Preparation Method

Prediseased NZB/NZW mice (urinary protein level

Dosage form

0, 10, 20, 30, 40 mg/kg twice daily for 240 days.

Applications

2 of 29 mice treated with the 40-mg/kg dose of fostamatinib demonstrated elevated proteinuria (urinary protein level >300 mg/dl), compared with 21 of 30 mice in the vehicle-treated group. All 29 mice treated with 40 mg/kg of R788 survived until study termination .

参考文献:

[1]: 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.
[2]: Bahjat F R, Pine P R, Reitsma A, et al. An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus[J]. Arthritis & Rheumatism, 2008, 58(5): 1433-1444.

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Fostamatinib (R788)

Fostamatinib (R788)详情

Background

Protocol

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