Signal Transduction Enzyme Inhibitors from Extremophilic Microbes as Anticancer A

嗜极微生物信号转导酶抑制剂作为抗癌 A

• 批准号: 8052902
• 负责人: ANDREA Anne STIERLE
• 金额: $ 20.97万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052902
• 关键词: Acids; Address; Adverse effects; American; Antineoplastic Agents; Area; Biological Assay; Biological Factors; Biomedical Research; Cancer cell line; Caspase-1; Cause of Death; Cell Line; Cytotoxic agent; Developmental Therapeutics Program; Diagnosis; Environment; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; Exhibits; Fermentation; Funding; Goals; Health; Human; Inorganic Sulfates; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Metals; Methodology; Microbe; Mining; Modality; National Cancer Institute; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Organism; Public Health; Research; Research Institute; Scheme; Signal Transduction; Source; Stromelysin 1; Structure; Students; Techniques; Testing; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; Water; Western World; anticancer activity; base; cancer type; cytotoxicity; drug discovery; in vitro activity; leukemia; meetings; microbial; microorganism; novel; novel strategies; programs; success; tool; wasting

DESCRIPTION (provided by applicant): The overall goal of this project is the discovery of new natural products with anticancer activity from extremophilic microbes isolated from an acid mine waste lake. Compounds will be isolated based on their ability to inhibit specific signal transduction enzymes that have been implicated in the onset and metastasis of several different types of cancer. Matrix metalloproteinase-3 (MMP-3) and caspase-1 (casp-1) have been shown to be up-regulated in certain cancers. For the past five years we have developed a bioassay-guided isolation scheme that has resulted in the isolation and purification of several novel compounds that inhibit one or both of these enzymes. The structures of these compounds were elucidated through spectral techniques. To establish a correlation between enzyme inhibition and anticancer activity, these pure enzyme inhibitors were submitted to the National Cancer Institute Developmental Therapy Program (NCI/DTP) for testing against 60 human cancer cell lines. This methodology has resulted in the isolation and identification of several lead compounds with nanomolar or low micromolar activity and high selectivity towards ovarian cancer, non-small cell lung cancer, and leukemia. Microbes isolated from acid mine waste have proven to be a rich source of previously unreported, bioactive metabolites. Preliminary studies, which have been funded through the National Institutes of Health-IDeA Networks of Biomedical Research Excellence (INBRE), yielded over 70 different microorganisms from the metal sulfate rich waters and deep basal sediment. Of the 30 microorganisms already examined in small pilot fermentation studies, over 50% of the extracts inhibited MMP-3 and/or Casp-1. In- depth exploration of five of these organisms has yielded several novel compounds including berkelic acid, which exhibited selective nanomolar activity against OVCAR-3 and berkeleydione which exhibited selective low micromolar activity against nonsmall cell lung cancer strain NCI-H460. With these early successes we would like to continue studying these microbes with the following specific aims: 1. Isolate compounds from targeted extremophilic microorganisms using signal transduction enzyme inhibition as an isolation guide. 2. Elucidate the structures of these compounds using spectroscopic or x-ray methodology. 3. Test active compounds in the NIH/DTP cell line screen to determine in vitro activity. 4. Send compounds with enzyme inhibitory activity and nanomolar - low micromolar activity against specific human cancer cell lines to Eisai Research Institute for further evaluation. 5. Involve undergraduate students in all aspects of microbial drug discovery This research has shown promise and the funds requested for this RO1 would be used to continue this exploration. It addresses a critical need area and combines both unique assay tools and a unique extreme environment for drug discovery. PUBLIC HEALTH RELEVANCE: Over 565,000 Americans are expected to die of cancer this year, and more than 2,437,000 new cancer cases are expected to be diagnosed. Despite our arsenal of anticancer agents, cancer is now the second leading cause of death in the western world. Unfortunately, current treatment modalities use cytotoxic agents that can cause deleterious side-effects. This application describes a novel approach to drug discovery, using signal transduction enzyme inhibition as a guide to the isolation of selective, potent anticancer agents from extremophilic microbes. Enzyme inhibitors will be tested by NCI/DTP against 60 human cancer cell lines and by Eisai Research Institute to determine anticancer activity. Novel compounds will help meet the increasing need for new treatment modalities with high selectivity and potency, and lower cytotoxicity than current treatment options.

描述（由申请人提供）：该项目的总体目标是从酸性矿山废湖中分离出的极端微生物中发现具有抗癌活性的新天然产物。化合物将根据其抑制特定信号转导酶的能力进行分离，这些酶与几种不同类型的癌症的发病和转移有关。基质金属蛋白酶-3 (MMP-3) 和 caspase-1 (casp-1) 已被证明在某些癌症中表达上调。在过去的五年中，我们开发了一种生物测定引导的分离方案，该方案已分离和纯化了几种抑制这些酶中一种或两种酶的新型化合物。通过光谱技术阐明了这些化合物的结构。为了建立酶抑制和抗癌活性之间的相关性，这些纯酶抑制剂被提交给美国国家癌症研究所发展治疗计划 (NCI/DTP)，以针对 60 种人类癌细胞系进行测试。该方法已分离和鉴定了几种具有纳摩尔或低微摩尔活性以及对卵巢癌、非小细胞肺癌和白血病具有高选择性的先导化合物。从酸性矿山废物中分离出的微生物已被证明是以前未报道的生物活性代谢物的丰富来源。初步研究由美国国立卫生研究院-IDeA 生物医学卓越研究网络 (INBRE) 资助，从富含金属硫酸盐的水域和深层基底沉积物中发现了 70 多种不同的微生物。在小型试点发酵研究中已检测的 30 种微生物中，超过 50% 的提取物抑制 MMP-3 和/或 Casp-1。对其中五种生物体的深入探索已经产生了几种新化合物，包括伯克酸（对OVCAR-3表现出选择性纳摩尔活性）和伯克二酮（对非小细胞肺癌菌株NCI-H460表现出选择性低微摩尔活性）。凭借这些早期的成功，我们希望继续研究这些微生物，以实现以下具体目标： 1. 使用信号转导酶抑制作为分离指导，从目标嗜极微生物中分离化合物。 2. 使用光谱或 X 射线方法阐明这些化合物的结构。 3. 在 NIH/DTP 细胞系筛选中测试活性化合物以确定体外活性。 4. 将具有酶抑制活性和针对特定人类癌细胞系的纳摩尔-低微摩尔活性的化合物发送至卫材研究所进行进一步评估。 5. 让本科生参与微生物药物发现的各个方面 这项研究已显示出前景，RO1 所需的资金将用于继续这项探索。它解决了一个关键需求领域，并结合了独特的分析工具和独特的药物发现极端环境。公共卫生相关性：今年预计将有超过 565,000 名美国人死于癌症，预计将诊断出超过 2,437,000 例新癌症病例。尽管我们拥有丰富的抗癌药物，癌症现在仍是西方世界第二大死亡原因。不幸的是，目前的治疗方式使用可能导致有害副作用的细胞毒性剂。该申请描述了一种药物发现的新方法，使用信号转导酶抑制作为从极端微生物中分离选择性、有效的抗癌药物的指导。 NCI/DTP 将针对 60 种人类癌细胞系对酶抑制剂进行测试，并由卫材研究所进行测试，以确定其抗癌活性。新型化合物将有助于满足对新治疗方式日益增长的需求，这些新治疗方式具有高选择性和效力，并且比目前的治疗方案具有更低的细胞毒性。