NCI Program for Natural Products Discovery - Cures

1. 总体进展a.列出计划的预期目标和结果。目的1。创建新技术，建立一个增强的NP预分馏库，适用于现代高通量靶向筛选程序。目标2。利用新的方法和文库扩大可培养微生物的化学多样性。目标3。为世界各地的筛选中心提供预分离库，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（隔离、结构解析、再供应）以加快转化过程。目标6。建立公共数据库和生物信息学平台，扩大投入，扩大影响。b.总结报告期内（21财年）取得的进展。1. 在2021财年，NPNPD增加了4,000个土壤真菌，其中2230个被镀，拍照和冷冻瓶（总共13,354个）用于长期使用。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测定，并进行了镀片、拍照和冷冻瓶（9份）长期使用。3. 预分离工作产生了7.7万个馏分，到2021年底，生产的总馏分将达到51万个。4. NPNPD镀了480万口井的馏分，供应给校外社区。5. NPNPD在2021年又执行了4个mta来接收预分馏样品（明尼苏达大学、多伦多大学、达拉斯德克萨斯大学、澳大利亚国立大学）。6. NPNPD还收到了另外4份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）。与NIAID完成了一项新的机构间协议。8. NPNPD还向研究实验室运送了47万份预分馏样品进行筛选。9. NPNPD化学实验室对预分离样品筛选中鉴定的生物活性组分进行了1386次二次纯化，并将30,000份高度纯化的样品送回筛选中心。2. 解决倡议和癌症登月计划的目标a.描述为实现倡议的目标和结果所取得的主要成就。生产50万份预分馏天然产品样品。已准备好384孔板，其中包含20,000,000个预分馏样品，准备发货。向公众发布了第一批32.6万个分数。在执行40个mta后，向校外筛选实验室运送了5,200,000个电镀筛选样品。NPNPD片段库的高通量筛选与沃尔特里德陆军研究所、国家推进转化科学中心（2个筛选）、阿斯特拉利康、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以及NCI癌症研究中心（4个筛选）共同完成。从NPNPD馏分库的筛选中鉴定出65,000个纯化的活性馏分。创建了新的微生物库，其中包括22000种美国土壤真菌和6500种澳大利亚海洋微生物。完成与国防部、NCATS、NCCIH、NIAID和CRADA与Astra Zeneca的协议。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，目前正在申请NCI专利。在德克萨斯大学圣安东尼奥分校、韩国生药学学会、NCI校内科研人员休养所、NCI癌症预防部、俄勒冈州立大学、胡德学院和国家促进转化科学中心发表了关于NPNPD的特邀演讲。在各自的期刊上发表了两篇论文。1. Gkovic T, Ruchirawat S, Kittakoop P, Grothaus PG, Evans JR, Britt JR, Newman DJ, Mahidol C， O'Keefe BR。一种新型双吡啶啉亚胺醌生物碱的分离纯化。植物化学学报，10(7):1647-1649,2011。2. Krushkall J, Negi S, Yee LM, Evans JR, Grkovic T, Palmisano A, Fang J, Sankaran H, McShane m, Zhao Y， O'Keefe BR NCI-60癌细胞组对天然产物的体外反应的分子基因组特征。中国生物医学工程学报，2015(2):391 - 396。b.关键成就如何实现推荐目标？关键成就表明，NPNPD已经创建并减少了自动化系统的实践，这些系统大大提高了支持药物发现的天然产物化学工作的速度和功能。它们还显示了校外研究团体的广泛“支持”，以及其他美国政府机构对NPNPD影响的扩展。NPNPD出版物在出版时受到高度追捧和特色，增加了该计划的知名度，并且每年都会收到关于NPNPD研讨会的多个请求。NPNPD正在实现其目标，即在药物发现项目中增加天然产物样本的使用，目前已完成多个筛选，已确定了生物活性天然产物。c.加强合作是癌症登月计划的主要目标。请描述该计划的协作活动（如鼓励协作的补充，网络之间的协作研究等）。NPNOD是高度协作的。总的来说，NPNPD已经收到了来自75个研究机构的请求，要求获得NPNPD镀分数。目前已执行了其中40项协定。这些都是NCI天然产物化学和校外筛选中心之间的合作。我们还完成了与几个美国政府机构的合作协议。我们越来越多地看到NPNPD组分筛选产生新的生物活性分子的结果，包括最近被NCI申请专利的一项发现。最后，我们成功地与Astra Zeneca进行了CRADA，以筛选针对肿瘤靶点的NPNPD组分，目前正在与诺华就CDA进行谈判。d.保健差距和各组织之间的伙伴关系等跨领域主题是癌症登月计划的主要组成部分。请描述该倡议是如何处理跨领域主题的？NPNPD已经在跨领域的NIH小组中进行合作，包括NIH HEAL倡议与NCATS、NCCIH和校外研究小组。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。美国国家海洋和大气管理局（NOAA）已经启动了另一项海洋收集RFA， NCCIH发布了一项全球天然产物核磁共振数据库RFA。我们还与NCI癌症预防部启动了一个联合项目，该部门将资助使用NPNPD分数的筛查项目。e.请提供关键产出（如出版物、员工发明报告、专利申请、认可（如研究奖励）或临床试验号）的详细信息？请注意，我们正在寻找关键/重要的输出，而不是一个全面的列表。1. 40名完成硕士学位（如哈佛大学、哥伦比亚大学、斯克里普斯大学、范德比尔特大学、普林斯顿大学等）4个已完成的多年机构间协议（NCCIH， NCATS， NIAID， WRAIR）目前与阿斯利康的CRADA [CRADA #03290-19]。4. 国立卫生研究院疼痛联盟获得2020年国立卫生研究院优秀奖。到目前为止，有五份出版物（都是在他们的封面上刊登的）

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*