SB 747651A dihydrochloride是一种新型的、具有口服活性的ATP竞争性丝裂原和应激激活激酶1（MSK1；IC₅₀=11nM）抑制剂。
Cas No.:1781882-72-1
Sample solution is provided at 25 µL, 10mM.
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SB 747651A dihydrochloride is a novel, orally active ATP-competitive inhibitor of mitogen- and stress-activated protein kinase 1 (MSK1; IC₅₀=11nM). SB 747651A dihydrochloride also effectively inhibits kinases such as PRK2, RSK1, p70S6K, and ROCK-II[1-2]. By suppressing RelA phosphorylation, SB 747651A dihydrochloride inhibits cancer cell invasion and is primarily used in research on inflammation and related immune disorders[3-4].
In vitro, SB 747651A dihydrochloride (1μM), either alone or in combination with cytarabine (Ara-C; 5μM), was applied to acute myeloid leukemia (AML) cell lines THP-1 and U937, as well as primary AML cells, for 24 hours. SB 747651A dihydrochloride significantly enhanced Ara-C-induced apoptosis, reduced cell viability, and induced cell cycle arrest at the G0/G1 phase, thereby increasing the chemosensitivity of AML cells to Ara-C[5]. SB 747651A dihydrochloride (2.5–20μM) pretreated human hepatoma HepG2-ADH cells for 4 hours, followed by ethanol (50mM) exposure for 2 hours. SB 747651A dihydrochloride significantly suppressed ethanol-induced Brf1 mRNA and protein expression, downregulated transcription of Brf1 downstream targets tRNALeu and 5S rRNA, and inhibited cell proliferation and colony formation in a dose- and time-dependent manner[6].
In vivo, SB 747651A dihydrochloride (25mg/kg/day) was administered intraperitoneally to tumor-bearing mice (implanted with T78 glioblastoma cells) five days a week for eight weeks, starting post-implantation. SB 747651A dihydrochloride significantly extended median survival and suppressed tumor growth[7]. SB 747651A dihydrochloride (5μM local perfusion or 3mg/kg intraperitoneal/intrathecal injection) was given to C57BL/6N mice subjected to CXCL2-induced inflammation. When administered 30 minutes before to 60 minutes after CXCL2 stimulation (or systemically 1 hour before CXCL2), SB 747651A dihydrochloride initially (1–2 hours) suppressed neutrophil transendothelial migration and tissue migration speed, but later (3–4 hours) promoted neutrophil extravasation and modulated Mac-1 integrin-dependent intravascular crawling[8].
References:
[1] Naqvi S, Macdonald A, McCoy CE, et al. Characterization of the cellular action of the MSK inhibitor SB-747651A. Biochem J. 2012 Jan 1;441(1):347-57.
[2] Bhat N, Park J, Zoghbi HY, et al. The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development. PLoS One. 2016 Dec 14;11(12):e0166703.
[3] Johnson J, Shi Z, Liu Y, et al. Inhibitors of NF-kappaB reverse cellular invasion and target gene upregulation in an experimental model of aggressive oral squamous cell carcinoma. Oral Oncol. 2014 May;50(5):468-77.
[4] Zhao C, Hui W, Fernandes MJ, et al. Lysophosphatidic acid-induced IL-8 secretion involves MSK1 and MSK2 mediated activation of CREB1 in human fibroblast-like synoviocytes. Biochem Pharmacol. 2014 Jul 1;90(1):62-72.
[5] Zhang S, Pan C, Shang Q, et al. Overexpressed mitogen-and stress-activated protein kinase 1 promotes the resistance of cytarabine in acute myeloid leukemia through brahma related gene 1-mediated upregulation of heme oxygenase-1. Eur J Pharmacol. 2022 Feb 15;917:174722.
[6] Lin M, Huang C, Ren W, et al. Mitogen- and Stress-Activated Protein Kinase 1 Mediates Alcohol-Upregulated Transcription of Brf1 and tRNA Genes to Cause Phenotypic Alteration. Oxid Med Cell Longev. 2020 Jun 27;2020:2067959.
[7] Knudsen AM, Boldt HB, Jakobsen EV, et al. The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas. Sci Rep. 2021 Mar 16;11(1):6066.
[8] Hossain M, Omran E, Xu N, et al. The Specific Mitogen- and Stress-Activated Protein Kinase MSK1 Inhibitor SB-747651A Modulates Chemokine-Induced Neutrophil Recruitment. Int J Mol Sci. 2017 Oct 17;18(10):2163.
SB 747651A dihydrochloride是一种新型的、具有口服活性的ATP竞争性丝裂原和应激激活激酶1（MSK1；IC₅₀=11nM）抑制剂。SB 747651A dihydrochloride还能有效抑制PRK2、RSK1、p70S6K和ROCK-II等激酶[1-2]。SB 747651A dihydrochloride可通过RelA的磷酸化抑制癌细胞的侵袭，SB 747651A dihydrochloride主要被用于炎症及相关免疫性疾病的研究[3-4]。
在体外，SB 747651A dihydrochloride（1μM）单独或联合阿糖胞苷（Ara-C；5μM）处理急性髓系白血病（AML）细胞系THP-1、U937及原代AML细胞24小时，SB 747651A dihydrochloride显著增强Ara-C诱导的细胞凋亡，并降低细胞活力；同时，SB 747651A dihydrochloride使细胞周期阻滞在G0/G1期，增强AML细胞对Ara-C的化疗敏感性[5]。SB 747651A dihydrochloride（2.5-20μM）预处理人肝癌HepG2-ADH细胞4小时，随后用乙醇（50mM）处理2小时，SB 747651A dihydrochloride显著抑制乙醇诱导的Brf1 mRNA和蛋白表达，并下调Brf1下游tRNALeu和5S rRNA的转录水平。SB 747651A dihydrochloride以剂量和时间依赖方式抑制细胞增殖和集落形成能力[6]。
在体内，SB 747651A dihydrochloride（25mg/kg/day）腹腔注射处理荷瘤（T78胶质母细胞瘤细胞）小鼠（从肿瘤植入后开始，每周5天，持续8周），SB 747651A dihydrochloride显著延长荷瘤小鼠的中位生存期，并减少肿瘤生长[7]。SB 747651A dihydrochloride（5μM灌注或3mg/kg腹腔/鞘内注射）处理CXCL2诱导炎症的C57BL/6N小鼠（在CXCL2刺激前30分钟至刺激后60分钟灌注给药，或CXCL2注射前1小时全身给药）SB 747651A dihydrochloride早期（1–2小时）抑制中性粒细胞跨内皮迁移和组织迁移速度，但晚期（3–4小时）促进中性粒细胞渗出，并调节整合素Mac-1依赖的血管内爬行[8]。
| Cell experiment [1]: | |
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Cell lines |
THP-1 and U937 cells (human acute myeloid leukemia cell lines), and primary AML cells from patients |
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Preparation Method |
Cells were cultured in RPMI-1640 supplemented with 10% fetal bovine serum (FBS) at 37°C, 5% CO₂. Cells were treated with SB 747651A dihydrochloride (1μM) for 24 hours, alone or in combination with cytarabine (Ara-C; 5μM). |
|
Reaction Conditions |
1μM; 24h. |
|
Applications |
SB 747651A dihydrochloride significantly enhanced Ara-C-induced apoptosis in AML cells and arrested the cell cycle at the G0/G1 phase. SB 747651A dihydrochloride also downregulated MSK1 expression and suppressed the MSK1-BRG1-HO-1 signaling axis, thereby reversing chemoresistance to Ara-C. |
| Animal experiment [2]: | |
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Animal models |
BALB/c nude mice with orthotopic glioblastoma xenografts (T78 cell line) |
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Preparation Method |
Mice were intraperitoneally administered SB 747651A dihydrochloride (25mg/kg) five days per week for eight weeks, starting immediately after tumor cell implantation. Survival and toxicity were monitored throughout the treatment period. |
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Dosage form |
25mg/kg; i.p.; Five days/week for eight weeks. |
|
Applications |
SB 747651A dihydrochloride treatment significantly prolonged median survival of glioblastoma-bearing mice (128 days vs. 112 days in controls) without inducing weight loss, behavioral changes, or pathological alterations in liver, kidney, or brain tissues. SB 747651A dihydrochloride showed no adverse effects on serum alanine transaminase activity or creatinine levels, indicating high tolerability and potential for long-term anticancer therapy. |
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References: |
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| Cas No. | 1781882-72-1 | SDF | |
| 化学名 | 4-(1-ethyl-7-((piperidin-4-ylamino)methyl)-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine dihydrochloride | ||
| Canonical SMILES | CCN1C2=C(CNC3CCNCC3)C=NC=C2N=C1C4=NON=C4N.Cl.Cl | ||
| 分子式 | C16H22N8O.2HCl | 分子量 | 415.32 |
| 溶解度 | <20.77mg/ml in Water; <20.77mg/ml in DMSO | 储存条件 | Store at 2-8°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 | 2.4078 mL | 12.0389 mL | 24.0778 mL |
| 5 mM | 481.6 μL | 2.4078 mL | 4.8156 mL |
| 10 mM | 240.8 μL | 1.2039 mL | 2.4078 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。
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