Tpl2 Kinase Inhibitor
(Synonyms: 4-[(3-氯-4-氟苯基)氨基]-6-[(3-吡啶甲基)氨基]-1,7-萘啶-3-甲腈) 目录号 : GC45067
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Tpl2 Kinase Inhibitor（TKI）是一种可透过细胞膜的萘啶化合物，作为Tpl2激酶强效可逆的，ATP竞争性的抑制剂。
Cas No.:871307-18-5
Sample solution is provided at 25 µL, 10mM.
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Tpl2 Kinase Inhibitor (TKI) is a cell-permeable naphthyridine compound that acts as a potent reversible and ATP-competitive inhibitor of Tpl2 kinase[1]. Tpl2 (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family that is upstream of MEK in the ERK pathway[2]. Tpl2 Kinase Inhibitor can inhibit mitogen-activated protein kinase, extracellular signal-regulated kinase, c-jun N-terminal kinase and STAT3 signaling pathway[3].
In vitro, pretreatment with 0-20μM Tpl2 Kinase Inhibitor for 30min dose-dependently and markedly suppressed arsenite-induced COX-2 promoter activity and expression, and substantially attenuated arsenite-induced PGE2 production in JB6 P+ mouse epidermal cells[4]. Treatment with 5-10uM Tpl2 Kinase Inhibitor for 30min inhibited the IL-17A-induced phosphorylation of MEK1/2, ERK1/2, JNK1/2 and c-Jun in JB6 Cl41 cells[3].
In vivo, administration of Tpl2 Kinase Inhibitor by daily intraperitoneal injection for 2 days (2mg/kg and 10mg/kg) dose-dependently protected mice from thrombocytopenia[5]. Beginning on day 2 of DSS-induced colitis, Tpl2 Kinase Inhibitor (2.5mg/kg/d; i.p.) for 5 days effectively reduced weight loss and improved colitis in mice[1].
References:
[1] Lawrenz M, Visekruna A, Kuhl A, et al. Genetic and pharmacological targeting of TPL-2 kinase ameliorates experimental colitis: a potential target for the treatment of Crohn's disease? Mucosal Immunology. 2012;5(2):129-139.
[2] Gavrin LK, Green N, Hu Y, et al. Inhibition of Tpl2 kinase and TNF-alpha production with 1,7-naphthyridine-3-carbonitriles: synthesis and structure-activity relationships. Bioorg Med Chem Lett. 2005;15(23):5288-5292.
[3] Kim G, Khanal P, Lim SC, et al. Interleukin-17 induces AP-1 activity and cellular transformation via upregulation of tumor progression locus 2 activity. Carcinogenesis. 2013;34(2):341-350.
[4] Lee KM, Lee KW, Bode AM, Lee HJ, Dong Z. Tpl2 is a key mediator of arsenite-induced signal transduction. Cancer Res. 2009;69(20):8043-8049.
[5] Kyrmizi I, Ioannou M, Hatziapostolou M, Tsichlis PN, Boumpas DT, Tassiulas I. Tpl2 kinase regulates FcγR signaling and immune thrombocytopenia in mice. J Leukoc Biol. 2013;94(4):751-757.
Tpl2 Kinase Inhibitor（TKI）是一种可透过细胞膜的萘啶化合物，作为Tpl2激酶强效可逆的，ATP竞争性的抑制剂[1]。Tpl2（Cot/MAP3K8）是MAP3K家族中的一种丝氨酸/苏氨酸激酶，位于ERK通路中MEK的上游[2]。Tpl2 Kinase Inhibitor可以抑制丝裂原活化蛋白激酶、细胞外信号调节激酶、c-jun N末端激酶和STAT3信号通路[3]。
体外实验中，0-20μM的Tpl2 Kinase Inhibitor预处理JB6 P+小鼠表皮细胞30分钟，以剂量依赖的方式显著抑制亚砷酸钠诱导的COX-2启动子活性和表达，并显著减弱亚砷酸钠诱导的PGE2生成[4]。5-10μM的Tpl2 Kinase Inhibitor处理30分钟可抑制IL-17A诱导的JB6 Cl41细胞中MEK1/2、ERK1/2、JNK1/2和c-Jun的磷酸化[3]。
体内实验中，连续两天腹腔注射Tpl2 Kinase Inhibitor（2mg/kg和10mg/kg）以剂量依赖的方式保护小鼠免受血小板减少症的影响[5]。从DSS诱导的结肠炎的第2天开始，连续5天腹腔注射TKI（2.5mg/kg/d）可有效抑制小鼠体重减轻并改善结肠炎[1]。
| Cell experiment [1]: | |
Cell lines | JB6 P+ mouse epidermal cell line |
Preparation Method | Cells were treated with Tpl2 Kinase Inhibitor (0, 5, 10, or 20μM) for 30min before being stimulated with 20μM arsenite for 12h. The level of COX-2 and β-actin proteins was determined by Western blot using specific antibodies. The relative activity was measured by luciferase assay. PGE2 generation was determined using the PGE2 assay kit. |
Reaction Conditions | 0, 5, 10, or 20μM; 30min |
Applications | Tpl2 Kinase Inhibitor markedly suppressed arsenite-induced COX-2 promoter activity and expression, and substantially attenuated arsenite-induced PGE2 production in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | C57/Bl6 mice |
Preparation Method | Mice were injected i.p. with escalating doses of the Tpl2 Kinase Inhibitor (2mg/kg and 10mg/kg). Each mouse received one injection/day for 2 sequential days. Simultaneously injected with IVIg (2g/kg) as positive control. 24h after the pretreatment with the Tpl2 Kinase Inhibitor or IVIg, the mice were injected i.p. with the anti-CD41 antibody (for construct thrombocytopenia) or with the isotype antibody control. Platelet counts were determined 24h later. |
Dosage form | 2mg/kg and 10mg/kg; i.p. |
Applications | The Tpl2 Kinase Inhibitor protected mice from thrombocytopenia in a dose-dependent manner, and its effect was superior to pretreatment with IVIg. |
References: | |
| Cas No. | 871307-18-5 | SDF | |
| 别名 | 4-[(3-氯-4-氟苯基)氨基]-6-[(3-吡啶甲基)氨基]-1,7-萘啶-3-甲腈 | ||
| Canonical SMILES | FC(C=C1)=C(Cl)C=C1NC2=C(C#N)C=NC(C=N3)=C2C=C3NCC4=CN=CC=C4 | ||
| 分子式 | C21H14ClFN6 | 分子量 | 404.8 |
| 溶解度 | DMF: 1 mg/ml,DMF:PBS(pH7.2) (1:2): 0.33 mg/ml,DMSO: 1 mg/ml | 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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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4704 mL | 12.3518 mL | 24.7036 mL |
| 5 mM | 494.1 μL | 2.4704 mL | 4.9407 mL |
| 10 mM | 247 μL | 1.2352 mL | 2.4704 mL |
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| 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 |
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| % 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，
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1. 首先保证母液是澄清的；
2.
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Quality Control & SDS
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- Purity: >95.00% Appearance: A solid
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