Hitting a dozen enzymes with one drug The adenosine monophosphate-activated protein kinase (AMPK) controls cellular energy status. AMPK is activated when energy levels fall. This stimulates adenosine triphosphate (ATP)-generating pathways that promote glucose uptake and inhibits ATP-consuming pathways associated with glucose synthesis. In principle, these effects would be beneficial in metabolic diseases, including diabetes. Pharmacological activation of AMPK has been challenging, however, because in mammals, the enzyme exists as 12 distinct complexes. Myers et al. describe an orally available compound (MK-8722) that activates all 12 complexes (see the Perspective by Hardie). In animal models, MK-8722 ameliorated diabetes, but it also caused enlargement of the heart. MK-8722 may be a useful tool compound for laboratory research on AMPK function. Science, this issue p. 507; see also p. 455 In animals, a drug activating all 12 isoforms of the energy regulator AMPK benefits metabolism but may pose heart risks. 5′-Adenosine monophosphate–activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722–mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.

中文翻译：

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全身性泛 AMPK 激活剂 MK-8722 可改善葡萄糖稳态但诱导心脏肥大

用一种药物击中十几种酶 一磷酸腺苷活化蛋白激酶 (AMPK) 控制细胞能量状态。当能量水平下降时，AMPK 被激活。这会刺激三磷酸腺苷 (ATP) 生成途径，促进葡萄糖摄取并抑制与葡萄糖合成相关的 ATP 消耗途径。原则上，这些作用将有益于代谢疾病，包括糖尿病。然而，AMPK 的药理学激活具有挑战性，因为在哺乳动物中，该酶以 12 种不同的复合物形式存在。迈尔斯等人。描述了一种可激活所有 12 种复合物的口服化合物 (MK-8722)（参见 Hardie 的观点）。在动物模型中，MK-8722 改善了糖尿病，但也导致心脏增大。MK-8722 可能是实验室研究 AMPK 功能的有用工具化合物。科学，这个问题 p。507; 另见第。455 在动物中，激活能量调节剂 AMPK 的所有 12 种异构体的药物有利于新陈代谢，但可能会带来心脏病风险。5'-磷酸腺苷活化蛋白激酶 (AMPK) 是真核生物能量稳态的主要调节剂。尽管经过了三年的研究，AMPK 的生物学作用及其作为药物靶点的潜力仍未完全了解，这主要是因为缺乏优化的药理学工具。我们开发了 MK-8722，一种有效的、直接的、所有 12 种哺乳动物 AMPK 复合物的变构激活剂。在啮齿动物和恒河猴中，骨骼肌中 MK-8722 介导的 AMPK 激活诱导了强大、持久、不依赖胰岛素​​的葡萄糖摄取和糖原合成，从而改善了血糖，并且没有低血糖的证据。这些影响跨物种传播，