Targeting metabolism in AML

AML 中的靶向代谢

• 批准号: 10514584
• 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/10514584
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Affect; Age; Alkaloids; Animals; Antineoplastic Agents; Biological Assay; Cells; Cessation of life; Chemistry; Complement; Cross Reactions; Development; Disease; Disease Progression; Drug Targeting; Enzyme Inhibition; 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 Study; Plants; Play; Population; Prognosis; Property; Proteins; Reporting; Role; Series; Solid Neoplasm; Solubility; Specificity; Sulfhydryl Compounds; System; TXN gene; Testing; Therapeutic; Toxic effect; Work; acute myeloid leukemia cell; analog; 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; pharmacologic; 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.

急性髓系白血病(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改变。 传统化疗药物对56岁以上患者的疗效较差，中位数为 存活不到一年，只有20%的人存活两年。论小说的发展 急切需要治疗急性髓细胞白血病的药物。我们之前鉴定了一种从植物中提取的生物碱 有望削弱AML细胞生长和存活的药物。通过医疗 通过化学努力，我们已经确定了一系列高效的一叶卡宾类似物 在人类急性髓细胞白血病的小鼠模型中有希望的活动。我们已经鉴定出这些化合物 抑制硫氧还蛋白还原酶，这会直接和显著地影响 新陈代谢。在这项拨款中，我们将研究硫氧还蛋白还原酶如何作为主要的 通过药理学和遗传学研究调节癌细胞新陈代谢。此外，我们 将进行铅优化化学，以确定具有改进的一叶嘌呤类似物 并在人急性髓系白血病小鼠模型上进行药理特性试验。希望这是一次 这项工作将导致AML治疗方法的改进，并对硫氧还蛋白如何产生新的理解 还原酶可以直接调节癌细胞的代谢。