NCI Program for Natural Products Discovery - Cures

NCI 天然产物发现计划 - 治愈

• 批准号: 10702716
• 负责人: Barry Okeefe
• 金额: $ 179.61万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702716
• 关键词: Academic Medical Centers; Actinobacteria class; Address; Agreement; Alkaloids; Antibiotics; Antimalarials; Antineoplastic Agents; Asian; Australia; Award; Back; Basic Science; Bioinformatics; Biological Process; CCR; Cancer cell line; Chemicals; Chemistry; Clinical Trials; Collaborations; Collection; Communities; Cooperative Research and Development Agreement; Country; Databases; Division of Cancer Prevention; Division of Cancer Treatment and Diagnosis; ESKAPE pathogens; Employee; Extramural Activities; Fermentation; Funding; Genetic; Genomics; Goals; Government Agencies; Health; Helping to End Addiction Long-term; Human; In Vitro; Institutes; Institution; Investments; Iowa; Joints; Journals; Koreans; Laboratories; Legal patent; Leishmaniasis; Libraries; Malignant Neoplasms; Manuscripts; Mediation; Medical Research; Methods; Microbe; Minnesota; Modernization; Molecular; NCI Center for Cancer Research; National Center for Advancing Translational Sciences; National Center for Complementary and Integrative Health; National Institute of Allergy and Infectious Disease; National Oceanic and Atmospheric Administration; Natural Products; Natural Products Chemistry; Ohio; Oncology; Oregon; Outcome; Output; Pain; Pediatric Hospitals; Pharmacognosy; Production; Publications; Publishing; Recommendation; Reporting; Research; Research Activity; Research Institute; Research Personnel; Resources; Sampling; Screening Result; Shipping; Ships; Societies; Soil; Source; Speed; Structure; System; Taxonomy; Technology; Technology Transfer; Texas; United States National Institutes of Health; Universities; Vial device; anticancer activity; anticancer research; bioactive natural products; college; drug development; drug discovery; fungus; health disparity; high throughput screening; invention; kinase inhibitor; microbial; microorganism culture; molecular oncology; new technology; novel; programs; public database; response; screening; screening program; translational pipeline

1. Overall progress a. List the expected goals and outcomes of the initiative. Aim 1. Create new technologies to build an enhanced NP pre-fractionated library amenable to modern high-throughput targeted screening programs. Aim 2. Expand the chemical diversity available to the public from culturable microorganisms with new methods and libraries. Aim 3. Provide the pre-fractionated library to screening centers worldwide to accelerate drug discovery. Aim 4. Provide high throughput screening support for researchers to enable targeted discovery efforts. Aim 5. Provide faster analytical resources (isolation, structure elucidation, re-supply) to expedite translational pipelines. Aim 6. Establish a public database and bioinformatics platform to broaden input and expand impact. b. Summarize progress that has been made in the reporting period (FY21). 1. In FY 2021 the NPNPD accrued an additional 4,000 soil fungi 2230 of which were plated, photographed, and cryo-vialed (13,354 total) for long term use. In addition, 410 large-scale fermentations and extractions were conducted. 2. Initiated the genetic sequencing and taxonomic determination of 1000 marine actinomycetes and 1000 marine fungi which are also being plated, photographed, and cryo-vialed (9 copies) for long term use. 3. Prefractionation efforts produced 77,000 fractions to bring the total factions produced to 510,000 by the end of 2021. 4. The NPNPD plated 4,800,000 wells of fractions to supply to the extramural community. 5. The NPNPD executed an additional 4 MTAs to receive pre-fractionated samples in 2021 (Univ. Minnesota, Univ. Toronto, Univ. Texas at Dallas, Australian National Univ.). 6. The NPNPD received an additional 4 requests for MTAs to receive NPNPD fractions (Princeton, Ohio State Univ., Tel Aviv Univ., Naval Medical Research Center 7. Completed a new interagency agreement with NIAID. 8. The NPNPD shipped an additional 470,000 pre-fractionated samples to research labs for screening. 9. The NPNPD Chemistry laboratory undertook 1,386 secondary purifications of identified bioactive fractions identified in screens of pre-fractionated samples and returned 30,000 highly purified samples back to screening centers. 2. Addressing initiative and Cancer Moonshot goals a. Describe key accomplishments that have been made towards achieving the Initiative's goals and outcomes. Production of 500,000 pre-fractionated natural product samples. Have prepared 384-well plates containing 20,000,000 pre-fractionated samples ready for shipping. Released first 326,000 fractions to the public. Shipped 5,200,000 plated screening samples to extramural screening laboratories after execution of 40 MTAs. High throughput screens of the NPNPD Fraction library completed with Walter Reed Army Institute of Research, National Center for Advancing Translational Sciences (2 screens), Astra Zeneca, National Institute of Allergy and Infectious Diseases, University of Iowa, Texas Children's Hospital and Baylor University, and the NCI Center for Cancer Research (4 screens). Produced 65,000 purified sub-fractions of active fractions identified in screens of the NPNPD fraction library. Created new microbial library with 22,000 U.S. soil fungi and 6500 marine microbes from Australia. Completed agreements with DOD, NCATS, NCCIH, NIAID and CRADA with Astra Zeneca. Transferred technologies to multiple extramural research centers. Identified a novel kinase inhibitor with potential anticancer activity currently being patented by the NCI. Presented invited talks on the NPNPD to the University of Texas San Antonio, the Korean Society of Pharmacognosy, NCI Intramural Scientific Investigators Retreat, NCI Division of Cancer Prevention, Oregon State University, Hood College, and the National Center for Advancing Translational Sciences. Published 2 manuscripts each featured on the cover of their respective journals. 1. Gkovic T, Ruchirawat S, Kittakoop P, Grothaus PG, Evans JR, Britt JR, Newman DJ, Mahidol C, O'Keefe BR. A New Bispyrroloiminoquinone Alkaloid From a Thai Collection of Clavelina sp. Asian J Org Chem 10(7):1647-1649, 2021. 2. Krushkall J, Negi S, Yee LM, Evans JR, Grkovic T, Palmisano A, Fang J, Sankaran H, McShane LM, Zhao Y, O'Keefe BR Molecular Genomic Features Associated with in Vitro Response of the NCI-60 Cancer Cell Line Panel to Natural Products. Molecular Oncology 15(2):381-406, 2021. b. How do key accomplishments address recommendation goals? The key accomplishments show that the NPNPD has created and reduced to practice the automated systems necessary to greatly increase the speed and functionality of natural products chemistry efforts in support of drug discovery. They also show broad "buy-in" by the extramural research community as well as extension of NPNPD impact by other U.S. Government agencies. NPNPD publications are highly sought and featured when published, increasing the visibility of the program and multiple requests for seminars on the NPNPD are received on a yearly basis. The NPNPD is achieving its goal of increasing the use of natural product samples in drug discovery programs with multiple screens now completed that have identified bioactive natural products. c. Enhancing collaboration is a major goal of the Cancer Moonshot. Please describe the initiative's collaboration activities (such as supplements to encourage collaboration, collaborative research between networks, etc.). The NPNOD is highly collaborative. Overall, the NPNPD has received requests from 75 research institutions to receive NPNPD plated fractions. Currently 40 of those agreements have been executed. Each of these is a collaboration between NCI natural products chemistry and extramural screening centers. We have also completed collaboration agreements with several U.S. Government agencies. We are increasingly seeing the results of screens with NPNPD fractions resulting in new bioactive molecules including a recent discovery being patented by the NCI. Finally, we successfully executed a CRADA with Astra Zeneca to screen NPNPD fractions against an oncology target and are currently negotiating a CDA with Novartis. d. Cross-cutting themes of health disparities and partnerships between organizations are major components of the Cancer Moonshot. Please describe how cross-cutting themes are being addressed within the initiative? The NPNPD is already collaborating in cross-cutting NIH groups including the NIH HEAL initiative with NCATS, NCCIH and extramural research groups. We are working with NIAID on antibiotic discovery against ESKAPE pathogens and with WRAIR on anti-malarial and anti-leishmaniasis agent discovery for the DOD. NOAA has initiated another RFA for the collection of marine collections and NCCIH issued an RFA for a global natural product NMR database. We also have initiated a joint program with the NCI Division of Cancer Prevention who will be funding screening projects using NPNPD fractions. e. Please provide details on key outputs (such as publications, Employees Invention Reports, patent applications, recognition (such as research awards), or clinical trial number)? Note that we are looking for key/important outputs and not a comprehensive list. 1. 40 completed MTAs (e.g. Harvard, Columbia, Scripps, Vanderbilt, Princeton, etc.) 2. Four completed multi-year interagency agreements (NCCIH, NCATS, NIAID, WRAIR) 3. One current CRADA with Astra Zeneca [CRADA #03290-19]. 4. NIH Merit Award in 2020 with NCCIH and NCATS for NIH Pain Consortium. 5. Five publications so far (all featured on the cover of thei *TRUNCATED*

一、总体进展列出该计划的预期目标和成果。目标 1. 创建新技术来构建增强的 NP 预分级文库，以适应现代高通量靶向筛选计划。目标 2. 通过新方法和库扩大公众可从可培养微生物中获得的化学多样性。目标 3. 向世界各地的筛选中心提供预分级文库，以加速药物发现。目标 4. 为研究人员提供高通量筛选支持，以实现有针对性的发现工作。目标 5. 提供更快的分析资源（分离、结构阐明、重新供应）以加快转化流程。目标6.建立公共数据库和生物信息平台，扩大投入，扩大影响。 b.总结报告期内（2021 财年）取得的进展。 1. 2021 财年，NPNPD 又收集了 4,000 株土壤真菌，其中 2230 株经过电镀、拍照和冷冻保存（总共 13,354 株）以供长期使用。此外，还进行了410次大规模发酵和提取。 2. 启动了1000种海洋放线菌和1000种海洋真菌的基因测序和分类学测定，并进行铺板、拍照和冻存（9份）以供长期使用。 3. 预分馏工作生产了 77,000 个馏分，到 2021 年底，生产的总馏分达到 510,000 个。 4. NPNPD 电镀了 4,800,000 口馏分井，供应给校外社区。 5. NPNPD 在 2021 年执行了另外 4 个 MTA，以接收预分割样本（明尼苏达大学、多伦多大学、德克萨斯大学达拉斯分校、澳大利亚国立大学）。 6. NPNPD 收到了另外 4 个 MTA 接收 NPNPD 分数的请求（普林斯顿大学、俄亥俄州立大学、特拉维夫大学、海军医学研究中心） 7. 与 NIAID 完成了新的机构间协议。 8. NPNPD 额外运送了 470,000预分馏样品送至研究实验室进行筛选 9. NPNPD 化学实验室对已鉴定的样品进行了 1,386 次二次纯化。预分馏样品筛选中鉴定出的生物活性组分，并将 30,000 份高度纯化的样品送回筛查中心 2. 实现倡议和癌症登月计划目标 a. 描述为实现该倡议的目标和成果而取得的主要成就。 - 已准备好含有 20,000,000 个预分馏样品的 384 孔板，可供首次发布。向公众发送 326,000 个馏分 在执行 40 个 MTA 后，向校外筛选实验室运送了 5,200,000 个平板筛选样品。 NPNPD 组分库的高通量筛选与沃尔特·里德陆军研究所、国家转化科学促进中心（2 个筛选）、阿斯利康、国家过敏和传染病研究所、爱荷华大学、德克萨斯儿童医院和贝勒大学共同完成，和 NCI 癌症研究中心（4 个屏幕）。产生了 65,000 个在 NPNPD 组分库筛选中鉴定的活性组分的纯化亚组分。创建了新的微生物库，其中包含 22,000 种美国土壤真菌和来自澳大利亚的 6500 种海洋微生物。与 DOD、NCATS、NCCIH、NIAID 以及 CRADA 与 Astra Zeneca 签署了协议。将技术转移到多个校外研究中心。 鉴定出一种具有潜在抗癌活性的新型激酶抑制剂，目前已获得 NCI 的专利。向德克萨斯大学圣安东尼奥分校、韩国生药学会、NCI 校内科学研究者静修会、NCI 癌症预防部门、俄勒冈州立大学、胡德学院和国家转化科学促进中心就 NPNPD 进行邀请演讲。发表了 2 篇手稿，每篇都出现在各自期刊的封面上。 1. Gkovic T、Ruchirawat S、Kittakoop P、Grothaus PG、Evans JR、Britt JR、Newman DJ、Mahidol C、O'Keefe BR。来自泰国 Clavelina sp 收藏的新双吡咯亚氨基醌生物碱。亚洲有机化学杂志 10(7):1647-1649, 2021。 2. Krushkall J、Negi S、Yee LM、Evans JR、Grkovic T、Palmisano A、Fang J、Sankaran H、McShane LM、Zhao Y、O'Keefe BR 与 NCI-60 癌细胞系组对天然产物的体外反应相关的分子基因组特征。分子肿瘤学 15(2):381-406, 2021。主要成就如何实现推荐目标？主要成就表明，NPNPD 已经创建并减少了实践必要的自动化系统，以大大提高支持药物发现的天然产物化学工作的速度和功能。它们还显示出校外研究界的广泛“支持”以及其他美国政府机构对 NPNPD 影响的扩大。 NPNPD 出版物一经出版就受到高度追捧和特色，提高了该计划的知名度，并且每年都会收到多次关于 NPNPD 研讨会的请求。 NPNPD 正在实现其目标，即增加天然产物样品在药物发现项目中的使用，现已完成多个筛选，确定了具有生物活性的天然产物。 c.加强合作是癌症登月计划的主要目标。请描述该倡议的协作活动（例如鼓励协作的补充、网络之间的协作研究等）。 NPNOD 具有高度协作性。总体而言，NPNPD 已收到 75 个研究机构提出的接收 NPNPD 镀层馏分的请求。目前，其中 40 份协议已得到执行。其中每一项都是 NCI 天然产物化学和校外筛选中心之间的合作。我们还与多个美国政府机构签署了合作协议。我们越来越多地看到 NPNPD 组分的筛选结果产生了新的生物活性分子，其中包括最近获得 NCI 专利的发现。最后，我们与阿斯利康成功执行了 CRADA，根据肿瘤学目标筛选 NPNPD 分数，目前正在与诺华就 CDA 进行谈判。 d.健康差异和组织之间伙伴关系的跨领域主题是癌症登月计划的主要组成部分。请描述该计划如何解决跨领域主题？ NPNPD 已经在跨领域的 NIH 小组中进行合作，包括与 NCATS、NCCIH 和校外研究小组的 NIH HEAL 计划。我们正在与 NIAID 合作开发针对 ESKAPE 病原体的抗生素，并与 WRAIR 合作为国防部开发抗疟疾和抗利什曼病药物。 NOAA 发起了另一项关于海洋收藏品收集的 RFA，NCCIH 发布了针对全球天然产物 NMR 数据库的 RFA。我们还与 NCI 癌症预防部门启动了一项联合计划，该计划将资助使用 NPNPD 分数的筛查项目。 e.请提供关键成果的详细信息（例如出版物、员工发明报告、专利申请、认可（例如研究奖项）或临床试验编号）？请注意，我们正在寻找关键/重要的输出，而不是完整的列表。 1. 40 份已完成的 MTA（例如哈佛、哥伦比亚、斯克里普斯、范德比尔特、普林斯顿等） 2. 4 份已完成的多年机构间协议（NCCIH、NCATS、NIAID、WRAIR） 3. 与 Astra Zeneca 签订的一份当前 CRADA [CRADA #03290 -19]。 4. NIH 疼痛联盟与 NCCIH 和 NCATS 共同荣获 2020 年 NIH 优异奖。 5. 迄今为止已发表五篇出版物（均出现在 i *TRUNCATED* 的封面上）