| 描述 |
Zapnometinib(PD0184264)是CI-1040的活性代谢物,是一种MEK抑制剂,IC50为5.7nm。Zapnometinib具有抗流感病毒的抗病毒活性和抗菌活性[1][2][3]。
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| 相关类别 |
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| 靶点 |
MEK:5.7 nM (IC50)
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| 体外研究 |
Zapnometinib(0.1 nM-1μM)抑制MEK,在无细胞激酶分析、A549、MDCK细胞和人PBMC中IC50分别为30.96 nM、357 nM和15 nM[1]。Zapnometinib(100μM；4 h)抑制人PBMC中离子霉素(PMA/I)诱导的ERK1/2磷酸化[1]。Zapnometinib(1-100μM)可降低静脉注射H1N1pdm09、H3N2的病毒滴度[1]。westernblot分析[1]细胞系：人PBMCs浓度：100μM孵育时间：4h结果：抑制离子霉素(PMA/I)-增加pERK1/2。
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| 体内研究 |
Zapnometinib(8.4-75 mg/kg/天；一天三次p.o.)可降低致命H1N1pdm09感染后的肺部病毒滴度并提高小鼠存活率[1]。Zapnometinib(150 mg/kg)通过静脉注射或口服途径在小鼠体内的AUC值分别为860.02和1953.68μg•h/mL[1]。动物模型：雌性C57BL/6小鼠(8周；21-24 g)感染H1N1pdm09[1]剂量：8.4,25,75 mg/kg/天(2.8,8.4,25 mg/kg)给药：P.o.每天三次结果：在75 mg/kg/天或25 mg/kg/天的剂量下,病毒滴度显著降低。
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| 参考文献 |
[1]. Laure M, et, al. Antiviral efficacy against influenza virus and pharmacokinetic analysis of a novel MEK-inhibitor, ATR-002, in cell culture and in the mouse model. Antiviral Res. 2020 Jun;178:104806. [2]. Hamza H, et, al. Improved in vitro Efficacy of Baloxavir Marboxil Against Influenza A Virus Infection by Combination Treatment With the MEK Inhibitor ATR-002. Front Microbiol. 2021 Feb 12;12:611958. [3]. Bruchhagen C, et, al. Metabolic conversion of CI-1040 turns a cellular MEK-inhibitor into an antibacterial compound. Sci Rep. 2018 Jun 14;8(1):9114.
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