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：血液恶性肿瘤，特别是白血病，是影响各种类型血细胞的癌症。 它们是全球最常见的癌症之一，占所有新发癌症的 10% 以上 一种特别具有挑战性的白血病形式是急性髓性白血病 (AML)，这是一种 成人白血病最常见的形式仍然很难治疗，并且通常与显着相关。 死亡率较高，尤其是老年患者。在全世界范围内，AML 每年影响大约 100 万人。 每年导致超过 150,000 人死亡，占美国所有癌症相关死亡的近 2%。 AML 的“治愈”率随着年龄的增长而急剧下降；60 岁以下患者的治愈率为 33%，年龄较大的患者则降至 10% 超过 60 岁。未接受任何治疗的患者（通常是由于太虚弱而无法耐受治疗）仍可维持生命 预期不到一年。 叶酸是为治疗淋巴源性白血病而开发的更重要的药物之一 抗代谢药甲氨蝶呤 (MTX) 主要通过靶向必需酶发挥其活性。 二氢叶酸还原酶（DHFR）是嘧啶和嘌呤从头合成的关键参与者。 然而，这一类重要的细胞对于快速分裂的癌细胞的增殖至关重要。 抗代谢药物在治疗 AML 方面的临床应用很少，MTX 是一种经典的抗叶酸药物，也是一种治疗 AML 的药物。 叶酸的类似物，一种带负电荷的维生素，必须主动转运到其所在的细胞中 聚谷氨酰化以获得最大活性和细胞保留，经典抗癌抗叶酸剂需要 相同的运输和酶促机制来实现其治疗潜力，因此，这些蛋白质 成为癌细胞获得耐药性的关键机制，最近另一种抗叶酸药物， 培美曲塞 (PMX) 已被证明对某些实体瘤的治疗有显着改善。 理论上，PMX 功效的提高是偶然“多靶点”的结果，其中其他叶酸 相关代谢途径中的依赖性酶也受到抑制。在本应用中，我们将追求。 开发新的抗叶酸剂，专为 AML 设计，反映 PMX 的多靶点性质，同时减少 与 MTX 和 PMX 等经典抗叶酸药物相关的副作用。 我们的工作重点是非经典抗叶酸剂、不需要叶酸主动转运的抑制剂或 最近，我们开始探索这些化合物的抗癌作用。 应用并发现该系列中的同系物对血液细胞表现出显着的活性 系，包括骨髓系，同时保持相对于其他组织的良好选择性。 (1) 针对多种 AML 亚型的先导抗叶酸药物的放大合成和分析，以及 (2) 评估 AML 动物模型中的药代动力学特征和有效性。