Inhibition of Eukaryotic Translation by Antitumor Natural Product Agelastatin A

抗肿瘤天然产物 Agelastatin A 对真核翻译的抑制作用

• 批准号: 8719703
• 负责人: Brandon T McClary
• 金额: $ 4.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719703
• 关键词: Affinity; Agelas; Alkaloids; Animals; Antineoplastic Agents; Antitumor Natural Products; Apoptosis; Binding; Binding Proteins; Biochemical; Biological Factors; Biotin; Cell Adhesion Inhibition; Cell Proliferation; Cell Survival; Chemicals; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Data; Detection; Dissection; Future; Glycogen Synthase Kinases; Glycoproteins; Goals; Knowledge; Label; Malignant Neoplasms; Marines; Methods; Microbe; Modification; Molecular; Molecular Mechanisms of Action; Molecular Target; Pharmaceutical Preparations; Plants; Play; Porifera; Positioning Attribute; Process; Proliferating; Protein Biosynthesis; Protein Translation Pathway; Proteins; Regulation; Reporting; Ribosomes; Role; Site; Source; Staging; Structure-Activity Relationship; Testing; Texas; Therapeutic; Translation Process; Translations; Variant; analog; base; cancer cell; chemotherapy; drug discovery; homoharringtonine; in vitro Assay; inhibitor/antagonist; insight; marine organism; novel; oroidin; osteopontin; public health relevance; small molecule; translation factor; tumor

DESCRIPTION (provided by applicant): The quest for novel anticancer drugs has led to a vast number of tumor inhibitory compounds from various natural sources including plants, animals, microbes, and marine organisms. One recently discovered antitumor natural product of marine origin is the structurally unique brominated oroidin alkaloid (-)-agelastatin A (AglA), derived fro the marine sponge Agelas dendromorpha [1]. The goal of this project is to elucidate a molecular target of AglA. In the current realm of drug discovery, there is no single method satisfactory for identifying protein targets of bioactive small molecules. By using both a "top-down" and "bottom up" approach, I expect to elucidate a target of the novel natural product AglA [2]. Based on preliminary data, I hypothesize that the site of action of AglA is a post-initiation stage of translation. Aim 1 serves to narrow down the site of perturbation and elucidate a molecular target by taking advantage of cellular and in vitro assays specific to eukaryotic protein translation. Aim 2 serves to identify a molecular target through direct chemical modification of AglA. This is significant because protein synthesis plays a huge role in cell survival, especially n fast-proliferating cancer cells. Several inhibitors of eukaryotic protein synthesis, including the translation elongation inhibitor homoharringtonine (Omacetaxine mepesuccinate), have entered the clinical stage, establishing translation as a promising target for chemotherapy [3]. Not only i this promising for future cancer therapeutics; perturbation of translation will allow us to dissect minute molecular details of the process, providing valuable insight into the eukaryotic ribosome and its components.

描述（由申请人提供）：对新型抗癌药物的追求导致了来自各种天然来源的大量肿瘤抑制性化合物，包括植物，动物，微生物和海洋生物。最近发现的海洋来源的抗肿瘤天然产物是结构上独特的溴溴素生物碱（ - ） - 艾氏素A（Agla），从海洋海绵agelas dendromorpha得出[1]。该项目的目的是阐明AGLA的分子靶标。在当前的药物发现领域中，没有一种方法令人满意地识别生物活性小分子的蛋白质靶标。通过使用“自上而下”和“自下而上”方法，我希望阐明新型天然产物AGLA的目标[2]。根据初步数据，我假设AGLA的作用部位是翻译后阶段。 AIM 1通过利用细胞和体外测定法对真核蛋白翻译特定的优势来缩小扰动位点并阐明分子靶标。 AIM 2通过直接化学修饰AGLA来识别分子靶标。这很重要，因为蛋白质合成在细胞存活中起着巨大的作用，尤其是n个快速增长的癌细胞。真核蛋白质合成的几种抑制剂，包括翻译伸长抑制剂同生丁氨酸（omacetaxine mepesuccinate），已经进入了临床阶段，确立了翻译作为化学疗法的有希望的靶标[3]。我不仅对未来的癌症治疗有希望；翻译的扰动将使我们能够剖析 该过程的微小分子细节，为真核核糖体及其成分提供了宝贵的见解。