A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis
A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis
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DOI：
10.1021/ml100143q
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发表时间：
2010-12-01
影响因子：
4.2
通讯作者：
Erion, Mark D.
中科院分区：
文献类型：
--
作者：
Gomez-Galeno, Jorge E.;Dang, Qun;Erion, Mark D.
amp活化蛋白激酶（AMPK）是一种调节细胞活性的异三聚体激酶。能量代谢通过影响能量消耗途径，如新生。脂质生物合成和葡萄糖生产以及能量产生途径，如脂质氧化和葡萄糖摄取。因此，激活AMPK的化合物代表了治疗高脂血症和2型糖尿病的潜在候选药物。对AMP模拟物专有文库的筛选发现，磷酸2与AMP的结构几乎没有相似之处，但能够以高效率(EC（50) = 6 nM vs AMP EC(50) = 6 μ M）和特异性激活AMPK。在高脂血症的细胞和动物模型中，磷酸2前药抑制新生脂肪生成。
AMP-activated protein kinase (AMPK) is a heterotrimeric kinase that regulates cellular. energy metabolism by affecting energy-consuming pathways such as de novo. lipid biosynthesis and glucose production as well as energy-producing pathways such as lipid oxidation and glucose uptake. Accordingly, compounds that activate AMPK represent potential drug candidates for the treatment of hyperlipidemia and type 2 diabetes. Screening of a proprietary library of AMP mimetics identified the phosphonic acid 2 that bears little structural resemblance to AMP but is capable of activating AMPK with high potency (EC(50) = 6 nM vs AMP EC(50) = 6 mu M) and specificity. Phosphonate prodrugs of 2 inhibited de novo lipogenesis In cellular and animal models of hyperlipidemia.