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*

1。总体进步a。列出该计划的预期目标和结果。目标1。创建新技术，以建立一个可容纳现代高通量目标筛查程序的增强的NP预分级图书馆。 AIM 2。通过新方法和图书馆从可培养的微生物中扩展公众可用的化学多样性。 AIM 3。提供预分级的图书馆，以筛查全球的筛查中心，以加速药物发现。 AIM 4。为研究人员提供高吞吐量筛查支持，以实现目标发现工作。 AIM 5。提供更快的分析资源（隔离，结构阐明，重新供应），以加快转化管道。目标6。建立一个公共数据库和生物信息学平台，以扩大输入并扩大影响。 b。总结报告期（FY21）已取得的进展。 1。在2021财年，NPNPD又加入了4,000种土壤真菌2230，其中镀上，拍照和冷冻水瓶（总计13,354）供长期使用。此外，进行了410种大规模发酵和提取。 2。启动了1000个海洋放线菌和1000种海洋真菌的遗传测序和分类测定，这些测序也正在镀上，拍照和冷冻瓶（9份），以供长期使用。 3.预分型工作产生了77,000个分数，以使总派系在2021年底之前产生了510,000个派系。 5。NPNPD执行了另外4个MTA，以在2021年接受预分量的样本（明尼苏达州大学，多伦多大学，多伦多，大学，德克萨斯州德克萨斯州德克萨斯州达拉斯，澳大利亚国家大学）。 6。NPNPD还收到了MTA的另外4个请求，要求MTA接收NPNPD分数（俄亥俄州普林斯顿州立大学，特拉维夫大学，海军医学研究中心7。与NIAID完成了一项新的互助协议。8。NPNPD进行了470,000个预分量的样品，用于筛查NUDER SPALES，用于筛选NPN 3. 9. 9. 9. 9。在预分级样本中鉴定出的次要净化，并将30,000个高度纯化的样品返回到筛选中心2。准备运输的样本向公众发布了326,000个分数。 NPNPD分数库的高吞吐量屏幕由沃尔特·里德陆军研究所，国家前进的转化科学中心（2个屏幕），阿斯特拉Zeneca，国家过敏和感染疾病研究所，爱荷华大学，德克萨斯大学儿童医院和贝勒大学以及NCI癌症研究中心（4个筛选）（4个筛选）。在NPNPD分数库中鉴定出的活性分数的65,000个纯化的子互动。创建了新的微生物图书馆，其中有22,000个美国土壤真菌和澳大利亚的6500个海洋微生物。与DOD，NCAT，NCCIH，NIAID和CRADA与Astra Zeneca达成了完成协议。将技术转移到多个壁外研究中心。 鉴定出一种新型的激酶抑制剂，其潜在的抗癌活性目前已获得NCI专利。邀请了关于NPNPD的邀请会谈得克萨斯大学圣安东尼奥大学，韩国药物学学会，NCI壁画内科学研究人员务虚会，NCI预防癌症预防司，俄勒冈州立大学，胡德学院，国家霍华大学和国家 /地区前进的翻译科学中心。出版了2个手稿，每个手稿都在各自的期刊的封面上出现。 1。GkovicT，Ruchirawat S，Kittakoop P，Grothaus PG，Evans JR，Britt JR，Newman DJ，Mahidol C，O'Keefe BR。来自泰国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.分子肿瘤学15（2）：381-406，2021。b。关键成就如何解决建议目标？关键成就表明，NPNPD已创建并减少了，以实践自动化系统，以极大地提高天然产品化学努力以支持药物发现的速度和功能。它们还显示了校外研究界的广泛“买入”，以及其他美国政府机构对NPNPD影响的扩展。 NPNPD出版物在发布时受到高度寻求和介绍，增加了该计划的可见性，并每年收到关于NPNPD研讨会的多个研讨会的请求。 NPNPD实现了将天然产品样品在药物发现程序中增加使用的目的，这些筛查现在已经完成了多个屏幕，这些屏幕已经鉴定出了生物活性天然产品。 c。加强协作是癌症月光下的主要目标。请描述该计划的合作活动（例如补充，以鼓励协作，网络之间的协作研究等）。 NPNOD是高度协作的。总体而言，NPNPD已收到75家研究机构的请求，以接收NPNPD镀的分数。目前已执行这些协议中的40个。这些都是NCI天然产品化学和壁外筛查中心之间的合作。我们还与几家美国政府机构完成了合作协议。我们越来越多地看到具有NPNPD级分的筛选结果，导致了新的生物活性分子，包括最近的发现已获得NCI专利。最后，我们成功地与Astra Zeneca执行了Crada，以针对肿瘤学目标进行筛选NPNPD的分数，并目前正在与Novartis协商CDA。 d。组织之间的健康差异和伙伴关系主题是癌症月光下的主要组成部分。请描述该倡议中如何解决跨裁切主题？ NPNPD已经在交叉切割NIH组中进行了合作，包括与NCAT，NCCIH和校外研究小组的NIH Heal倡议。我们正在与NIAID合作研究针对Eskape病原体的抗生素发现，并与DOD的抗疟疾和抗leishmaniasis剂发现有关。 NOAA发起了另一项RFA，用于收集海洋收藏，NCCIH为全球天然产品NMR数据库发布了RFA。我们还与NCI预防癌症部门启动了联合计划，该计划将使用NPNPD分数为筛查项目提供资金。 e。请提供有关关键产出的详细信息（例如出版物，员工发明报告，专利申请，认可（例如研究奖）或临床试验号）？请注意，我们正在寻找关键/重要输出，而不是全面的列表。 1。40完成了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。四个完成了多年的多年跨机构协议（NCCIH，NCATS，NCATS，NIAID，wrair）3。一个目前与Astra Zeneca的Crada [Crada＃03290-19]。 4。2020年的NIH值得奖，并获得了NCCIH和NCAT的NIH疼痛财团。 5。到目前为止的五个出版物（全部都在Thei *截断 *的封面上出现。