Targeting metabolism in AML

AML 中的靶向代谢

• 批准号: 10293585
• 负责人: David Wald
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293585
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Affect; Age; Alkaloids; Animals; Antineoplastic Agents; Biological Assay; Cells; Cessation of life; Chemistry; Complement; Development; Disease; Drug Targeting; Enzymes; Exhibits; Family; General Population; Genetic; Genetic study; Glutathione Reductase; Glycolysis; Grant; Growth; Hematopoietic; Human; Immunodeficient Mouse; Impairment; In Vitro; Individual; Inferior; Lead; Measurement; Mediating; Metabolic; Metabolism; Military Personnel; Modeling; Molecular Target; Morbidity - disease rate; Mus; Normal Cell; Outcome; Oxidation-Reduction; Oxidoreductase; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Plants; Play; Population; Prognosis; Property; Proteins; Reporting; Role; Series; Solid Neoplasm; Solubility; Specificity; Sulfhydryl Compounds; System; TXN gene; Testing; Therapeutic; Time; Toxic effect; Work; acute myeloid leukemia cell; analog; base; cell growth; clinical application; enzyme activity; glutathione peroxidase; hazard; human model; improved; in vivo; inhibitor; lead optimization; leukemia; metabolomics; mitochondrial metabolism; mortality; mouse model; nanomolar; neoplastic cell; novel; novel therapeutics; therapeutic development; thioredoxin reductase; tumor metabolism

Acute myeloid leukemia (AML) is the most common type of acute leukemia affecting adults, but unfortunately there has been no change in standard therapy for most patients in over 40 years. Traditional chemotherapeutics exhibit poor efficacy in patients over the age of 56, with a median survival of less than one year and only 20% surviving two years. The development of novel therapies for AML is urgently needed. We previously identified a plant derived alkaloid as a promising agent that impaired the growth and survival of AML cells. Through medicinal chemistry efforts, we have identified a series of securinine analogues with high potency and promising activity in mouse models of human AML. We have identified that these compounds inhibit the enzyme thioredoxin reductase and that this leads to direct and marked effects on metabolism. In this grant, we will investigate how thioredoxin reductase functions as a major regulator of cancer cell metabolism through pharmacologic and genetic studies. In addition, we will perform lead optimization chemistry to identify securinine analogues with improved pharmacologic properties and test them in mouse models of human AML. It is hoped that this work will lead to improved therapies for AML and a novel understanding of how thioredoxin reductase can directly regulate cancer cell metabolism.

急性髓性白血病（AML）是影响成人的最常见的急性白血病类型，但 不幸的是，40多年来，大多数患者的标准治疗没有变化。 传统的化疗药物在56岁以上的患者中表现出较差的疗效， 存活不到一年，只有20%的人存活两年。开发新型 急需要AML的治疗。我们以前确定了一种植物衍生的生物碱， 有希望的代理，损害AML细胞的生长和存活。通过药用 化学的努力，我们已经确定了一系列具有高效力的一叶秋碱类似物， 在人类AML的小鼠模型中有希望的活性。我们发现这些化合物 抑制酶硫氧还蛋白还原酶，这导致直接和显着的影响， 新陈代谢.在这项资助中，我们将研究硫氧还蛋白还原酶如何作为一种主要的 通过药理学和遗传学研究发现，它是癌细胞代谢的调节剂。另外我们 将进行铅优化化学，以确定一叶秋碱类似物与改善 药理学特性，并在人AML的小鼠模型中测试它们。希望这一 这项工作将改善AML的治疗方法，并对硫氧还蛋白如何 还原酶可以直接调节癌细胞的代谢。