4'-Substituted nucleoside analogs as anticancer drugs

4-取代核苷类似物作为抗癌药物

• 批准号: 7585807
• 负责人: JOHN A SECRIST
• 金额: $ 45.62万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-12 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585807
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Adult; Animal Model; Animals; Antineoplastic Agents; Applications Grants; Area; Biochemical; Biochemical Pharmacology; Biological; Biological Models; Carbohydrates; Carbon; Cell Culture Techniques; Cell Death; Cellular Membrane; Childhood Acute Lymphocytic Leukemia; Cladribine; Clinical; Clinical Trials; Clofarabine; Computer Simulation; Cytosine; DNA-Directed DNA Polymerase; Data; Deoxycytidine Kinase; Development; Disease; Elements; Enzymes; Evaluation; FDA approved; Fluorine; Goals; Half-Life; Hematologic Neoplasms; Human; In Vitro; Investigation; Knowledge; Laboratories; Lead; Learning; Literature; Malignant neoplasm of pancreas; Metabolic; Metabolic Pathway; Metabolism; Mind; Modification; Mus; New Agents; Non-Small-Cell Lung Carcinoma; Normal Cell; Nucleic Acids; Nucleosides; Oxygen; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Positioning Attribute; Property; Purines; Pyrimidine; Pyrimidine Nucleosides; Pyrimidines; Research; Research Personnel; Ribonucleotide Reductase; Selection Criteria; Series; Solid Neoplasm; Structural Protein; Structure; Study models; Sulfur; Thionucleosides; Toxic effect; Tumor Cell Line; analog; anticancer activity; base; cancer therapy; chemical stability; cytotoxic; cytotoxicity; cytotoxicity test; design; drug discovery; enzyme substrate; gemcitabine; improved; in vivo; meetings; neoplastic cell; novel; nucleoside analog; purine; research clinical testing; structural biology; tetrahydrofuran; tripolyphosphate; tumor; tumor xenograft

DESCRIPTION (provided by applicant): The goal of this application is to rationally design, synthesize, and evaluate certain nucleoside analogs in an effort to discover new agents for the treatment of solid tumors as well as hematological malignancies. The key investigators of this project have been involved in this endeavor for many years and have recently been responsible for the discovery of a new drug (clofarabine) that was approved by the FDA for the treatment of childhood acute lymphocytic leukemia in December of 2004 and is currently being evaluated in adult clinical trials for activity in solid tumors and hematological malignancies. Recently, we have discovered a lead compound that is modified at the 2'- and 4'-positions that has demonstrated excellent activity against solid tumor xenografts in mice. Only a few analogs in this series have been made with anticancer activity as the disease target, and it is the goal of this proposal to thoroughly evaluate the potential of this type of modification. The application consists of two specific aims. In aim 1 we will design and synthesize novel nucleoside analogs with modifications at the 4'-carbon. The target compounds are rationally designed based on our extensive knowledge of nucleoside metabolism, the analogs that are currently used in the treatment of cancer, available protein structural data, computational modeling with dCyd kinase and those compounds that have been made in the past by us and others. All new compounds will be tested for cytotoxicity against a panel of human solid tumor cell lines. Cytotoxic compounds will be evaluated for toxicity to normal cells, and those compounds with significant selectivity will be synthesized in sufficient quantities for in vivo studies to determine antitumor efficacy against numerous human solid tumor xenografts. In specific aim 2 we will evaluate the metabolism and mechanism of action of new agents with promising activity so that we can learn how these compounds differ from existing agents. The results of the biological evaluations will be used in the iterative rational design of new compounds. This grant application is a highly integrated effort involving expertise in the design and synthesis of nucleoside analogs, the biochemical evaluation of the metabolism and mechanism of action of nucleoside analogs, and the evaluation of new agents in human tumor xenografts. The grant application is focused on the discovery of new anticancer agents based on an established anticancer drug class, and is expected to lead to a clinical candidate as well as to increase our understanding of the mechanisms of action of this important class. In this proposal we will design, synthesize, and evaluate new nucleoside analogs as anticancer agents based upon a new lead compound with activity in animal model systems. The key investigators of this project have been involved in anticancer drug discovery for many years and have recently been responsible for the discovery of a new drug (clofarabine), which was recently approved by the FDA for the treatment of childhood acute lymphocytic leukemia and is currently being evaluated in adult clinical trials for activity in solid tumors and hematological malignancies.

描述（由申请人提供）： 该应用的目的是合理设计，合成和评估某些核苷类似物，以发现用于治疗实体瘤以及血液学恶性肿瘤的新药物。该项目的主要研究人员已经参与了这项工作多年，最近负责发现一种新药（克洛法拉滨），该药物在2004年12月获得了FDA批准的治疗儿童急性淋巴细胞性白血病，并且是目前正在成人临床试验中评估实体瘤和血液恶性肿瘤的活性。最近，我们发现了一种在2'-和4'位置进行了修饰的铅化合物，该化合物在小鼠中对实体瘤异种移植物的活性出色。本系列中只有几个类似物是抗癌活性作为疾病靶标的，这是该提案的目的是彻底评估这种类型的修饰的潜力。该应用程序由两个具体目标组成。在AIM 1中，我们将设计和合成在4-碳的修饰的新型核苷类似物。靶化合物是基于我们对核苷代谢的广泛了解，当前用于癌症治疗的类似物，可用的蛋白质结构数据，使用DCYD激酶的计算建模以及我们过去和我们过去和我们过去制造的化合物的计算建模的类似物以及其他的。所有新化合物将针对人类实体瘤细胞系的细胞毒性进行测试。将评估细胞毒性化合物的对正常细胞的毒性，并将具有显着选择性的化合物以足够量的体内研究合成，以确定针对许多人类实体瘤异种移植物的抗肿瘤疗效。在特定目标2中，我们将评估具有有希望的活动的新代理的代谢和作用机理，以便我们可以了解这些化合物与现有剂的不同。生物学评估的结果将用于新化合物的迭代合理设计。该赠款的应用是一种高度综合的工作，涉及核苷类似物的设计和合成，对核苷类似物的代谢和作用机理的生化评估以及人类肿瘤异种移植物中新药物的评估。该赠款的应用集中在基于既定的抗癌药物类别的新抗癌药物上的发现，并有望导致临床候选者，并提高我们对这一重要阶级作用机制的理解。在此提案中，我们将根据具有动物模型系统活性的新铅化合物设计，合成和评估新的核苷类似物作为抗癌剂。该项目的主要研究人员已经参与了抗癌药物发现已有多年了，最近负责发现一种新药（克洛法拉滨），该药物最近被FDA批准用于治疗儿童急性淋巴细胞性白血病，并且目前是在成人临床试验中评估实体瘤和血液系统恶性肿瘤的活性。