Targeting metabolism in AML

AML 中的靶向代谢

基本信息

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
项目类别：
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

项目摘要

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.

急性髓样白血病（AML）是影响成年人的最常见类型的急性白血病，但不幸的是，对于40多年来，大多数患者的标准疗法没有变化。传统的化学治疗药在56岁以上的患者中表现出较差的功效，中位数不到一年的生存，只有20％的生存。小说的发展迫切需要AML的疗法。我们先前以前确定了一种衍生的生物碱的植物有希望的药物会损害AML细胞的生长和存活。通过药用化学努力，我们已经确定了一系列具有高效力的证券类似物，在人AML小鼠模型中有希望的活动。我们已经确定了这些化合物抑制硫氧还蛋白还原酶的酶，这会导致直接和明显的影响代谢。在这笔赠款中，我们将研究硫氧还蛋白还原酶如何发挥作用通过药理学和遗传研究调节癌细胞代谢。另外，我们将执行铅优化化学，以识别具有改进的证券类似物药理学特性并在人AML的小鼠模型中测试它们。希望这个工作将导致改善AML的疗法，并对硫氧还蛋白的新了解还原酶可以直接调节癌细胞代谢。