Development of novel adenosine monophosphate-activated protein kinase activators.
Development of novel adenosine monophosphate-activated protein kinase activators.
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DOI：
10.1021/jm901773d
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发表时间：
2010-03-25
影响因子：
7.3
通讯作者：
Chen CS
中科院分区：
文献类型：
--
作者：
Guh JH;Chang WL;Yang J;Lee SL;Wei S;Wang D;Kulp SK;Chen CS
鉴于噻唑烷二酮介导过氧化物酶体增殖物激活受体（PPAR）γ非依赖性激活腺苷单磷酸激活蛋白激酶（AMPK）和抑制白细胞介素（IL）-6产生的独特能力，我们对内部基于噻唑烷二酮的重点化合物库进行了筛选，以鉴定具有这些双重药理活性的新型药物。与AMPK和雷帕霉素靶的哺乳动物同系物（即，分别磷酸化AMPK和p70核糖体蛋白S6激酶），和IL-6/IL-6受体信号传导（即，使用脂多糖（LPS）刺激的THP-1人巨噬细胞中的IL-6产生以及信号转导子和转录激活子3磷酸化）来筛选该化合物文库，这导致鉴定化合物53（N-{4-[3-（1-甲基环己基甲基）-2，4-二氧代-噻唑烷-5-亚基-甲基]-苯基}-4-硝基-3-三氟甲基-苯磺酰胺）作为先导剂。有证据表明，这种药物诱导的LPS刺激的IL-6产生的抑制可归因于AMPK激活。此外，在C-26结肠腺癌细胞中证实了化合物53介导的AMPK活化，表明其不是细胞系特异性事件。
In light of the unique ability of thiazolidinediones to mediate peroxisome proliferator-activated receptor (PPAR)γ-independent activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of interleukin (IL)-6 production, we conducted a screening of an in-house, thiazolidinedione-based focused compound library to identify novel agents with these dual pharmacological activities. Cell-based assays pertinent to the activation status of AMPK and mammalian homolog of target of rapamycin (i.e., phosphorylation of AMPK and p70 ribosomal protein S6 kinase, respectively), and IL-6/IL-6 receptor signaling (i.e., IL-6 production and signal transducer and activator of transcription 3 phosphorylation, respectively) in lipopolysaccharide (LPS)-stimulated THP-1 human macrophages were used to screen this compound library, which led to the identification of compound 53 (N-{4-[3-(1-Methylcyclohexylmethyl)-2,4-dioxo-thiazolidin-5-ylidene-methyl]-phenyl}-4-nitro-3-trifluoromethyl-benzenesulfonamide) as the lead agent. Evidence indicates that this drug-induced suppression of LPS-stimulated IL-6 production was attributable to AMPK activation. Furthermore, compound 53-mediated AMPK activation was demonstrated in C-26 colon adenocarcinoma cells, indicating that it is not a cell line-specific event.