Antimetabolites for Acute Myeloid Leukemias

急性髓系白血病的抗代谢药

• 批准号: 9909414
• 负责人: Dennis L. Wright
• 金额: $ 30万
• 依托单位: QUERCUS MOLECULAR DESIGN, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-11 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909414
• 关键词: Accounting; Active Biological Transport; Acute Myelocytic Leukemia; Address; Adult; Affect; Age; Allogenic; Animal Model; Animals; Antimetabolites; Ara-C; Blood Cells; Cancer cell line; Cell Line; Cells; Cessation of life; Charge; Chemical Exposure; Chemotherapy and/or radiation; Child; Connecticut; Daunorubicin; Development; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Disease; Dose; Dose-Limiting; Drug Kinetics; Drug resistance; Drug toxicity; Dysmyelopoietic Syndromes; Effectiveness; Elderly; Enzymes; Evaluation; Folic Acid; Folic Acid Antagonists; Follow-Up Studies; Formulation; Foundations; Future; Goals; Growth; HL-60 Cells; Hematologic Neoplasms; Hematology; Hematopoietic Neoplasms; Human; Immunotherapy; Injections; Interleukin-2; Joints; Lead; Life Expectancy; Link; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Metabolic Pathway; Methotrexate; Modification; Mus; Myelogenous; Myeloid Leukemia; Nature; Neoadjuvant Therapy; No-Observed-Adverse-Effect Level; Pancytopenia; Pathway interactions; Patients; Pemetrexed; Pharmaceutical Preparations; Phase; Population; Positioning Attribute; Proteins; Purines; Pyrimidine; Radiation therapy; Relapse; Resistance; Route; Series; Small Business Technology Transfer Research; Solid Neoplasm; Source; Stem cell transplant; Surveys; Survival Rate; System; Testing; Therapeutic; Tissues; Toxic effect; Universities; Vitamins; Work; Xenograft Model; acute myeloid leukemia cell; adult leukemia; anti-cancer; antimicrobial; base; cancer cell; cancer diagnosis; chemotherapy; clinical application; design; drug disposition; efficacy study; falls; hematopoietic tissue; improved; in vivo; in vivo evaluation; inhibitor/antagonist; interest; lead candidate; leukemia; metabolomics; mortality; mouse model; older patient; preclinical evaluation; prevent; public health relevance; scale up; screening panel; standard of care; stem; therapy design

Abstract: Hematological malignancies, specifically leukemias, are cancers affecting various types of blood cells. They are among the most common cancers worldwide and account for more than 10% of all new cancer diagnoses. One particularly challenging form of leukemia is Acute Myelogenous Leukemia (AML), which is the most common form of adult leukemia. AML is still very difficult to treat and typically associated with dramatically higher mortality rates, especially in older patients. Worldwide, AML affects roughly 1 million people per year and is responsible for >150,000 deaths per year, accounting for nearly 2% of all cancer-related deaths in the US. The ‘cure’ rate of AML falls dramatically with age; 33% for patients under 60, falling to 10% for patients older than 60. Patients receiving no treatment, typically due to being too weak to tolerate therapy, have a life expectancy of less than one year. One of the more significant drugs developed for the treatment of lymphoid derived leukemias is the folate antimetabolite methotrexate (MTX). MTX exerts its activity primarily through targeting the essential enzyme dihydrofolate reductase (DHFR). DHFR is a key player in the de novo synthesis of both pyrimidine and purine building blocks crucial for the propagation of rapidly dividing cancer cells. However, this important class of antimetabolites has found very little clinical application in treating AML. MTX is a classical antifolate and an analog of folic acid, a highly negatively charged vitamin that must be actively transported into cells where it is polyglutamylated for maximum activity and cellular retention. The classical anticancer antifolates require the same transport and enzymatic machinery to achieve their therapeutic potential and, as such, these proteins become the key mechanisms through which cancer cells achieve resistance. Recently another antifolate, pemetrexed (PMX), has been shown to be a substantial improvement in the treatment of some solid tumors. It is theorized that PMX’s improved efficacy is a consequence of incidental ‘multi-targeting’ whereby other folate- dependent enzymes in associated metabolic pathways are also inhibited. In this application, we will pursue the development of new antifolates, designed for AML that mirror the multi-targeting nature of PMX while reducing the liabilities associated with classical antifolates like MTX and PMX. Our work has focused on non-classical antifolates, inhibitors that do not require folic acid active transport or enzymatic modification to achieve efficacy. Recently, we have begun to explore these compounds for anti-cancer application and discovered congeners in this series that display remarkable activity against hematological cell lines, including myeloid lines, while maintaining good selectivity over other tissues. This application focuses on (1) scale-up synthesis and profiling of the lead antifolate against a diverse panel of AML subtypes and (2) evaluation of pharmacokinetic profile and effectiveness in an animal model of AML.

摘要：血液学恶性肿瘤，特别是白血病，是影响各种血液细胞的癌症。 它们是全球最常见的癌症之一，占所有新癌症的10％以上 诊断。白血病的一种特别挑战形式是急性髓性白血病（AML），这是 成人白血病的最常见形式。 AML仍然很难治疗，并且通常与 较高的死亡率，尤其是在老年患者中。全球，AML每年影响大约100万人 每年造成> 150,000人死亡，占美国与癌症相关的所有死亡人数的近2％。 随着年龄的增长，AML的“治愈率”急剧下降； 60岁以下患者的33％，年龄较大的患者跌至10％ 超过60个。没有接受治疗的患者，通常是由于太虚弱而无法忍受治疗， 期望不到一年。 用于治疗淋巴样性白血病的最重要的药物之一是叶酸 抗代谢物方法替代（MTX）。 MTX通过靶向必需酶发挥其主要的活性 二氢叶酸还原（DHFR）。 DHFR是从头合成嘧啶和嘌呤的关键参与者 构建障碍对于迅速分裂的癌细胞的传播至关重要。但是，这一重要类 抗代谢物在治疗AML方面几乎没有临床应用。 MTX是经典的抗叶酸和 叶酸的类似物，叶酸，一种高度负电荷的维生素，必须积极地转运到其所在的细胞中 聚谷氨酰化以最大程度的活性和细胞保留。经典抗癌药需要 相同的运输和酶促机械，以实现其治疗潜力，因此，这些蛋白质 成为癌细胞获得抗性的关键机制。最近另一个抗叶酸， Pemetrexed（PMX）已被证明在某些实体瘤的治疗方面有了很大的改善。 理论上认为PMX的提高效率是偶然的“多目标”的结果 相关代谢途径中的依赖酶也受到抑制。在此应用程序中，我们将追求 开发新的抗臭虫，为AML设计，它反映了PMX的多目标性质 与MTX和PMX等经典抗细胞相关的负债。 我们的工作集中于非经典抗染料，不需要叶酸活性转运的抑制剂或 酶促修饰以达到效率。最近，我们已经开始探索抗癌的这些化合物 在本系列中的应用并发现了对血液学细胞的出色活性的同类物 线，包括髓样线，同时保持对其他组织的良好选择性。此应用程序重点 （1）针对AML亚型潜水面板的抗叶酸铅抗叶酸的扩大合成和分析和（2） 在AML动物模型中评估药代动力学特征和有效性。