Fostamatinib (R788)
(Synonyms: 福他替尼; R788) 目录号 : GC11044
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。
Cas No.:901119-35-5
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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| Cell experiment [1]: | |
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Cell lines |
Head and neck squamous cell carcinoma (HNSCC) HN4, HN6, HN30, SCC9, SCC25 and CAL27 cell lines |
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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. |
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Reaction Conditions |
0-106 nM for 72 hours |
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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]: | |
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Animal models |
Female NZB/NZW mice |
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Preparation Method |
Prediseased NZB/NZW mice (urinary protein level |
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Dosage form |
0, 10, 20, 30, 40 mg/kg twice daily for 240 days. |
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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 . |
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References: [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. |
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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] .
| Cas No. | 901119-35-5 | SDF | |
| 别名 | 福他替尼; R788 | ||
| 化学名 | [6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate | ||
| Canonical SMILES | CC1(C(=O)N(C2=C(O1)C=CC(=N2)NC3=NC(=NC=C3F)NC4=CC(=C(C(=C4)OC)OC)OC)COP(=O)(O)O)C | ||
| 分子式 | C23H26FN6O9P | 分子量 | 580.46 |
| 溶解度 | ≥ 100.4mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7228 mL | 8.6139 mL | 17.2277 mL |
| 5 mM | 0.3446 mL | 1.7228 mL | 3.4455 mL |
| 10 mM | 0.1723 mL | 0.8614 mL | 1.7228 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Fostamatinib, a Syk-kinase inhibitor, does not affect methotrexate pharmacokinetics in patients with rheumatoid arthritis
J Clin Pharmacol2011 Sep;51(9):1310-8.PMID: 21209239DOI: 10.1177/0091270010381496
Fostamatinib (R788) is being investigated as an add-on therapy for the treatment of rheumatoid arthritis (RA) in patients with inadequate response to methotrexate (MTX). This study evaluated the potential pharmacokinetic interaction between R788 and MTX. Sixteen RA subjects on a stable weekly MTX regimen were enrolled and received MTX on days 1 and 8. Twelve subjects received 100 mg of R788 orally, and 4 subjects received a matching placebo twice daily from days 4 to 8 and once daily on days 3 and 9. Blood samples were collected on days 1 and 8 for MTX and 7-hydroxymethotrexate (7-OH-MTX), and days 3 and 9 for R788 and its active metabolite, R406. MTX and 7-OH-MTX pharmacokinetic parameters were similar on days 1 and 8. In the R788 group, the mean day 8 to day 1 ratios (90% confidence intervals) of maximum concentration and area under the plasma concentration-time curve estimates were 1.01 (0.85-1.20) and 1.12 (0.90-1.40) for MTX and 1.06 (0.82-1.35) and 1.06 (0.83-1.36) for 7-OH-MTX, respectively. Urinary excretion of MTX and 7-OH-MTX was also similar with or without R788, averaging 58% to 69% and 4% to 5% of the MTX dose, respectively. The data suggest that there is no clinically significant pharmacokinetic interaction of R788 and MTX in RA patients.
Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases
Expert Opin Investig Drugs2022 Mar;31(3):291-303.PMID: 35130124DOI: 10.1080/13543784.2022.2040014
Introduction: Autoimmune diseases (ADs) are disorders induced by multiple inflammatory mediators, in which immune system attacks healthy tissues and triggers tissue injury. Targeted regulation of the activity of kinases that influence inflammation is one of the major therapies for ADs. Recently, investigational spleen tyrosine kinase (SYK) inhibitors have shown encouraging results in the AD therapy.
Areas covered: This article provides a background on autoimmune diseases and provides an update on investigational SYK inhibitors. This literature review was conducted by searching publications about investigational SYK inhibitors in the treatment of ADs from experimental to clinical studies. The search terms used were SYK inhibitors, R406, fostamatinib (R788), P505-15 (PRT062607), entospletinib (GS-9973), R112, lanraplenib (GS-9876), cerdulatinib, R343, BAY-61-3606, GSK compound 143 (GSK143), R211, SKI-G-618, SKI-O-85, ER-27319, YM193306, RO9021 in conjunction with autoimmune disease using electronic databases including PubMed, EMBASE, MEDLINE and Google Scholar.
Expert opinion: SYK inhibitors are promising drugs with unique advantages and acceptable tolerability and safety for the treatment of ADs. However, the difficulties in developing highly selective SYK inhibitors and the unknown effects are challenges. Long-term and real-world data are essential to determine the risk-benefit ratio and true role of SYK inhibitors in the therapy of ADs.
Effects of fostamatinib (R788), an oral spleen tyrosine kinase inhibitor, on health-related quality of life in patients with active rheumatoid arthritis: analyses of patient-reported outcomes from a randomized, double-blind, placebo-controlled trial
J Rheumatol2013 Apr;40(4):369-78.PMID: 23378467DOI: 10.3899/jrheum.120923
Objective: To assess the influence of fostamatinib on patient-reported outcomes (PRO) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX).
Methods: Patients taking background MTX (N = 457) were enrolled in a phase II clinical trial (NCT00665925) and randomized equally to placebo, fostamatinib 100 mg twice daily (bid), or fostamatinib 150 mg once daily (qd) for 24 weeks. Self-administered PRO measures included pain, patient's global assessment (PtGA) of disease activity, physical function, health-related quality of life (HRQOL), and fatigue. Mean change from baseline and a responder analysis of the proportion of patients achieving a minimal clinically important difference were determined.
Results: At Week 24, there were statistically significant improvements in pain, PtGA, physical function, fatigue, and the physical component summary of the Medical Outcomes Study Short Form-36 (SF-36) for fostamatinib 100 mg bid compared with placebo. Mean (standard error) changes from baseline in the fostamatinib 100 mg bid group versus the placebo group were -31.3 (2.45) versus -17.8 (2.45), p < 0.001 for pain; -29.1 (2.26) versus -16.7 (2.42), p < 0.001 for PtGA; -0.647 (0.064) versus -0.343 (0.062), p < 0.001 for physical function; 7.40 (1.00) versus 4.50 (0.94), p < 0.05 for fatigue; 8.52 (0.77) versus 4.90 (0.78), p < 0.01 for SF-36 physical component score; and 3.99 (0.93) versus 3.71 (0.99), p = 0.83 for SF-36 mental component score. Patients receiving fostamatinib 150 mg qd showed improvements in some PRO, including physical function.
Conclusion: Patients treated with fostamatinib 100 mg bid showed significant improvements in HRQOL outcomes.
The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the E籿 TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling
Blood2010 Dec 2;116(23):4894-905.PMID: 20716772DOI: 10.1182/blood-2010-03-275180
Inhibition of antigen-dependent B-cell receptor (BCR) signaling is considered a promising therapeutic approach in chronic lymphocytic leukemia (CLL), but experimental in vivo evidence to support this view is still lacking. We have now investigated whether inhibition of BCR signaling with the selective Syk inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias that develop in the E籿TCL1 transgenic mouse model of CLL. Similarly to human CLL, these leukemias express stereotyped BCRs that react with autoantigens exposed on the surface of senescent or apoptotic cells, suggesting that they are antigen driven. We show that R788 effectively inhibits BCR signaling in vivo, resulting in reduced proliferation and survival of the malignant B cells and significantly prolonged survival of the treated animals. The growth-inhibitory effect of R788 occurs despite the relatively modest cytotoxic effect in vitro and is independent of basal Syk activity, suggesting that R788 functions primarily by inhibiting antigen-dependent BCR signals. Importantly, the effect of R788 was found to be selective for the malignant clones, as no disturbance in the production of normal B lymphocytes was observed. Collectively, these data provide further rationale for clinical trials with R788 in CLL and establish the BCR-signaling pathway as an important therapeutic target in this disease.
The status of fostamatinib in the treatment of rheumatoid arthritis
Expert Rev Clin Immunol2012 Sep;8(7):609-15.PMID: 23078058DOI: 10.1586/eci.12.63
Fostamatinib (R788) is a prodrug rapidly converted to its active metabolite on oral administration. This (known as R406) is a potent inhibitor of spleen tyrosine kinase, required for the expression of a number of proinflammatory cytokines. Fostamatinib has shown significantly superior efficacy (when compared with placebo) in the control of patients with rheumatoid arthritis not responding to methotrexate in Phase II clinical trials. Treatment emergent adverse events with a higher frequency than in those on placebo included diarrhea, hypertension, urinary tract infections, neutropenia and elevated transaminases. The studied doses have shown a linear pharmacokinetic pattern and the administration of methotrexate does not affect it. Fostamatinib may have a role in the therapy of patients with rheumatoid arthritis with poor response to conventional therapy. If these results are confirmed once Phase III studies are completed, it may find a place in the evolving treatment algorithm for rheumatoid arthritis.