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化学情報
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Synonyms | Tamatinib Fosdium | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
| 化学式 | C23H24FN6O9P.2Na |
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| 分子量 | 624.42 | CAS No. | 1025687-58-4 | |
| Solubility (25°C)* | 体外 | 5%TFA | 4.25 mg/mL (6.8 mM) | |
| DMSO | 0.4 mg/mL warmed with 50ºC water bath (0.64 mM) | |||
| Water | Insoluble | |||
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* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. |
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溶剤液（一定の濃度）を調合する
生物活性
| 製品説明 | Fostamatinib disodium (R788, Tamatinib Fosdium), a prodrug of the active metabolite R406, is a Syk inhibitor with IC50 of 41 nM in a cell-free assay, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. Phase 3. |
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| in vitro | R935788 is a methylene phosphate prodrug of R406, which can be rapidly converted to R406 in vivo. R406 (in vitro active form of R935788) selectively inhibits Syk-dependent signaling with EC50 values ranging from 33 nM to 171 nM, more potently than Syk-independent pathways in different cells. [1] R406 inhibits cellular proliferation of a variety of diffuse large B-cell lymphoma (DLBCL) cell lines with EC50 values ranging from 0.8 μM to 8.1 μM. [2] R406 treatment reduces basal phosphorylation of BLNK, Akt, glycogen synthase kinase-3 (GSK-3), forkhead box O (FOXO) and ERK not only in cells with high (TCL-002) but also in cells with low levels of phosphorylated Syk (TCL1-551). In addition, R406 completely inhibits the anti-IgM induced Bcr signal in TCL1 leukemias. Despite the higher levels of constitutively active Syk in TCL1 leukemias, R406 is not selectively cytotoxic to the leukemic cells. [3] |
| in vivo | Given that plasma half-life of R406 in mice is less than 2 hours, R935788 is administered in 3 divided doses at 3-hour intervals to provide continuous Syk inhibition during each day of treatment, mimicking the longer plasma half-life in humans (15 hours). Despite the relatively modest cytotoxic effect in vitro, R935788 significantly inhibits the proliferation and survival of leukemic cell in vivo, which is associated with the blocking of antigen-dependent B-cell receptor (Bcr) signaling rather than inhibition of constitutive Syk activity. R935788 treatment at 80 mg/kg/day for 18-21 days potently inhibits tumor growth of TCL1-002, TCL1-551 and TCL1-870 in mice with undetectable leukemic CD5+/B220+ cells at the last day of treatment, significantly prolongs the survival of the treated mice with median survival increased from 45/46 days to 170/172 days, and completely eradicates the malignant cells in a substantial proportion of mice after a 6-month follow-up period without affecting the production of normal B lymphocytes. R935788 treatment also induces an early and transient migration of both normal and malignant B cells from spleen and lymph nodes to peripheral blood, which is subsequently followed by selective growth inhibition of the malignant B-cell population. In addition, R935788 is also effective against spontaneously developing TCL1 leukemias in Eμ-TCL1 transgenic mice. [3] |
| 特徴 | Clinically used oral formulation of R406. |
プロトコル(参考用のみ)
| キナーゼアッセイ | In vitro fluorescence polarization kinase assays | |
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| R406 (in vitro active form of R935788) is serially diluted in DMSO and then diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg/mL acetylated BGG). ATP and substrate in kinase buffer are added at room temperature, resulting in a final DMSO concentration on 0.2%. The kinase reactions are performed in a final volume of 20 μL containing 5 μM HS1 peptide substrate and 4 μM ATP and started by addition of 0.125 ng of Syk in kinase buffer. The reaction is allowed to proceed for 40 minutes at room temperature. The reaction is stopped by the addition of 20 μL of PTK quench mix containing EDTA/anti-phosphotyrosine antibody (1× final)/fluorescent phosphopeptide tracer (0.5× final) diluted in FP Dilution Buffer. The plate is incubated for 30 minutes in the dark at room temperature and then read on a Polarion fluorescence polarization plate reader. Data is converted to determine the amount of phosphopeptide present using a calibration curve generated by competition with the phosphopeptide competitor provided in the Tyrosine Kinase Assay Kit. For IC50 determination, R406 is tested at eleven concentrations in duplicate and curve-fitting is performed by non-linear regression analysis using Prism GraphPad Software. | ||
| 細胞アッセイ | 細胞株 | TCL1-002, TCL1-252, TCL1-551, TCL1-870, and TCL1-540 |
| 濃度 | Dissolved in DMSO, final concentrations ~10 μM | |
| 反応時間 | 48 hours | |
| 実験の流れ | Cells are exposed to increasing concentrations of R406 (in vitro active form of R935788) for 48 hours. The percentage of apoptotic cells is determined by double staining with propidium iodide (PI) and annexin-A5–FITC conjugate. Ki-67 staining is performed with the FITC mouse anti–Ki-67 set. Samples are analyzed on a FACSCalibur flow cytometer with CellQuest Version 3.3 software. |
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| 動物実験 | 動物モデル | B6/C3H F1 female mice intraperitoneally injected with TCL1-002, TCL1-551, or TCL1-870 leukemia cells, and Eμ-TCL1 transgenic mice |
| 投薬量 | 80 mg/kg/day | |
| 投与方法 | Intraperitoneal administration in 3 divided doses at 3-hour intervals | |
参考
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カスタマーフィードバック
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Data from [Data independently produced by , , Clin Cancer Res, 2015, 21(11): 2538-45]
Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：
| Syk Inhibition Reprograms Tumor-Associated Macrophages and Overcomes Gemcitabine-Induced Immunosuppression in Pancreatic Ductal Adenocarcinoma [ Cancer Res, 2023, 83(16):2675-2689] | PubMed: 37306759 |
| C-type lectin-like receptor 2 specifies a functionally distinct subpopulation within phenotypically defined hematopoietic stem cell population that contribute to emergent megakaryopoiesis [ Int J Hematol, 2022, 10.1007/s12185-021-03220-9] | PubMed: 35106701 |
| Optimizing drug inhibition of IgE-mediated anaphylaxis in mice [ J Allergy Clin Immunol, 2021, S0091-6749(21)00979-9] | PubMed: 34186142 |
| Acute Kidney Injury Induced Lupus Exacerbation Through the Enhanced Neutrophil Extracellular Traps (and Apoptosis) in Fcgr2b Deficient Lupus Mice With Renal Ischemia Reperfusion Injury [ Front Immunol, 2021, 12:669162] | PubMed: 34248948 |
| Combinatorial Efficacy of Entospletinib and Chemotherapy in Patient-Derived Xenograft Models of Infant Acute Lymphoblastic Leukemia [ Haematologica, 2020, 15;haematol2019241729] | PubMed: 32414848 |
| Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis [ JCI Insight, 2020, 5(19)139930] | PubMed: 32853177 |
| Syk Inhibitor Attenuates Polymicrobial Sepsis in FcgRIIb-Deficient Lupus Mouse Model, the Impact of Lupus Characteristics in Sepsis [ J Innate Immun, 2020, 1-19] | PubMed: 32927460 |
| Transcriptomics-Based Drug Repurposing Approach Identifies Novel Drugs against Sorafenib-Resistant Hepatocellular Carcinoma [ Cancers (Basel), 2020, 12(10)E2730] | PubMed: 32977582 |
| Syk inhibitor attenuates inflammation in lupus mice from FcgRIIb deficiency but not in pristane induction: the influence of lupus pathogenesis on the therapeutic effect [ Lupus, 2020, 29(10):1248-1262] | PubMed: 32700597 |
| Effects of Inhibitors against Syk-BTK-PI3K Signaling on Platelet Function [ ScholarsArchive@OSU, 2020, 51] | PubMed: N/A |
長期の保管のために-20°Cの下で製品を保ってください。
人間や獣医の診断であるか治療的な使用のためにでない。
各々の製品のための特定の保管と取扱い情報は、製品データシートの上で示されます。大部分のSelleck製品は、推薦された状況の下で安定です。製品は、推薦された保管温度と異なる温度で、時々出荷されます。長期の保管のために必要とされてそれと異なる温度で、多くの製品は、短期もので安定です。品質を維持するが、夜通しの積荷のために最も経済的な貯蔵状況を用いてあなたの送料を保存する状況の下に、製品が出荷されることを、我々は確実とします。製品の受領と同時に、製品データシートの上で貯蔵推薦に従ってください。