Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Genes Dev. 2018 Jul 1;32(13-14):944-952. doi: 10.1101/gad.314658.118. Epub 2018 Jun 26.
The levels of copper, which is an essential element in living organisms, are under tight homeostatic control. Inactivating mutations in ATP7B, a P-type Cu-ATPase that functions in copper excretion, promote aberrant accumulation of the metal, primarily the in liver and brain. This condition underlies Wilson's disease, a severe autosomal recessive disorder characterized by profound hepatic and neurological deficits. Current treatment regimens rely on the use of broad specificity metal chelators as "decoppering" agents; however, there are side effects that limit their effectiveness. Here, we present the characterization of DPM-1001 {methyl 4-[7-hydroxy-10,13-dimethyl-3-({4-[(pyridin-2-ylmethyl)amino]butyl}amino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl] pentanoate} as a potent and highly selective chelator of copper that is orally bioavailable. Treatment of cell models, including fibroblasts derived from Wilson's disease patients, eliminated adverse effects associated with copper accumulation. Furthermore, treatment of the toxic milk mouse model of Wilson's disease with DPM-1001 lowered the levels of copper in the liver and brain, removing excess copper by excretion in the feces while ameliorating symptoms associated with the disease. These data suggest that it may be worthwhile to investigate DPM-1001 further as a new therapeutic agent for the treatment of Wilson's disease, with potential for application in other indications associated with elevated copper, including cancer and neurodegenerative diseases.
铜是生物体内必需的元素，其水平受到严格的体内平衡控制。ATP7B 的失活突变，一种 P 型 Cu-ATP 酶，其功能是铜排泄，促进金属的异常积累，主要是在肝脏和大脑中。这种情况是威尔逊病的基础，威尔逊病是一种严重的常染色体隐性遗传疾病，其特征是严重的肝脏和神经功能缺陷。目前的治疗方案依赖于使用广谱特异性金属螯合剂作为“脱铜”剂；然而，存在副作用限制了它们的有效性。在这里，我们介绍了 DPM-1001（[7-羟基-10,13-二甲基-3-[[4-[[(吡啶-2-基)甲基]氨基]丁基]氨基]十六氢-1H-环戊[a]菲-17-基]戊酸甲酯）作为一种有效的、高度选择性的铜螯合剂的特性，该螯合剂可口服生物利用。对包括来自威尔逊病患者的成纤维细胞在内的细胞模型进行治疗，消除了与铜积累相关的不良反应。此外，用 DPM-1001 治疗威尔逊病的毒性牛奶小鼠模型降低了肝脏和大脑中的铜水平，通过粪便排泄去除多余的铜，同时改善与疾病相关的症状。这些数据表明，进一步研究 DPM-1001 作为治疗威尔逊病的新治疗剂可能是值得的，它可能有潜力应用于其他与铜升高相关的适应症，包括癌症和神经退行性疾病。
