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]。