NCI Program for Natural Products Discovery - Cures

NCI 天然产物发现计划 - 治愈

• 批准号: 10926365
• 负责人: Barry Okeefe
• 金额: $ 81.82万
• 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/10926365
• 关键词: Acceleration; Actinobacteria class; Address; Adenosine; Africa; Agreement; Antibiotics; Antimalarials; Antineoplastic Agents; Australia; Back; Basic Science; Biochemical; Bioinformatics; Biological Process; Brazil; CCR; Chemicals; Chemistry; Chicago; Collaborations; Collection; Communicable Diseases; Communities; Cooperative Research and Development Agreement; Country; Crystallography; Cyclic Peptides; Data; Databases; Dimerization; Disease; Division of Cancer Prevention; ESKAPE pathogens; Enzyme Inhibitor Drugs; Evaluation; Extramural Activities; Fermentation; Fractionation; Funding; Genetic; Genomics; Goals; Government Agencies; Grant; Health; Helping to End Addiction Long-term; Human; Illinois; Interest Group; Investments; Joints; Journals; Korea; Laboratories; Legal patent; Leishmaniasis; Libraries; Macao; Malignant Neoplasms; Manuscripts; Medical center; Methods; Microbe; Modernization; National Cancer Advisory Board; National Cancer Institute; 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; North Carolina; Oncology; Outcome; Periodicity; Production; Protein Kinase A Inhibitor; Publications; Publishing; Recommendation; Reporting; Research; Research Activity; Research Personnel; Resources; Sampling; Screening Result; Shipping; Soil; Source; Speed; Structure; Sweden; System; Taxonomy; Technology; Technology Transfer; United States National Institutes of Health; Universities; Vial device; Virginia; anticancer activity; anticancer research; artificial neural network; bioactive natural products; drug development; drug discovery; empowerment; fungus; health disparity; high throughput screening; improved; kinase inhibitor; marine; medical schools; microbial; microorganism; natural antimicrobial; new technology; novel; programs; proto-oncogene protein c-cbl; public database; 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 (FY22). 1. In FY 2022 the NPNPD reached a level of 18,000 soil fungi which were plated, photographed, and cryo-vialed for long term use. In addition, 410 large-scale fermentations and extractions were conducted. 2. The genetic sequencing and taxonomic determination of 1000 marine actinomycetes and 1000 marine fungi (which are also being plated, photographed, and cryo-vialed for long term use) was also completed. 3. Prefractionation efforts produced 70,000 fractions to bring the total factions produced to 580,000 by the end of 2022. 4. The NPNPD plated 5,000,000 wells of fractions to supply to the extramural community. 5. The NPNPD currently has 10 executed collaboration agreements, 2 CRADAs, 5 CDAs, and an additional 19 MTAs to receive pre-fractionated samples. 6. The NPNPD received an additional 7 requests for MTAs to receive NPNPD fractions in 2022. 7. Initiated a new interagency agreement with NIAID and continued IAAs with NCCIH and NCATS. Initiated a new joint program with the Division of Cancer Prevention. Also initiated new CRADA with the University of Illinois at Chicago and a Collaboration Agreement with Novartis. 8. The NPNPD shipped an additional 1,900,000 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 580,000 pre-fractionated natural product samples. Have prepared 384-well plates containing 20,000,000 pre-fractionated samples ready for shipping. Released first 500,000 fractions to the public. Shipped 7,200,000 plated screening samples to extramural screening laboratories after execution of 50 MTAs. Produced 80,000 purified sub-fractions of active fractions identified in screens of the NPNPD fraction library. Created new microbial library with 24,000 U.S. soil fungi and 6500 marine microbes from Australia. Transferred technologies to multiple extramural research centers (S. Africa, Brazil, Korea, Sweden). Identified a novel kinase inhibitor with potential anticancer activity that has been patented by the NCI. Identified a novel cyclic peptide that is the first allosteric inhibitor of the enzyme TDP1 which haas been patented by the NCI and is the subject of a collaboration agreement with Genentech. Presented invited talks on the NPNPD to the Virginia Polytechnic Institute and State University, Harvard Medical School, University of Macau, University of Sao Paulo (Brazil), NIAID Drug Development Interest Group, University of North Carolina at Greensboro, National Center for Complementary and Integrative Health, Universities of Pretoria, Western Cape, Cape Town and Rhodes (S. Africa), and the National Cancer Advisory Board. Published 4 manuscripts 3 of which featured on the cover of their respective journals [Evans JR, Akee RK, Chanana S, McConachie GD, Thornburg CC, Grkovic T, O'Keefe BR. National Cancer Institute (NCI) Program for Natural Product Discovery: Exploring NCI-60 Screening Data of Natural Product Samples with Artificial Neural Networks. ACS Omega. 8(10):9250-9256, 2023; Wilson BAP, Li N, Martinez Fiesco JA, Dalilian M, Wang D, Smith EA, Wamiru A, Shah R, Goncharova EI, Beutler JA, Grkovic T, Zhang P, O'Keefe BR. Biochemical Discovery, Intracellular Evaluation, and Crystallographic Characterization of Synthetic and Natural Product Adenosine 3',5'-Cyclic Monophosphate-Dependent Protein Kinase A (PKA) Inhibitors. ACS Pharmacol Transl Sci. 6(4):633-650, 2023.; Khong QT, Li D, Wilson BAP, Ranguelova K, Dalilian M, Smith EA, Wamiru A, Goncharova EI, Grkovic T, Voeller D, Lipkowitz S, Schnermann MJ, O'Keefe BR, Du L. Photochemical Dimerization of Plakinidine B Leads to Potent Inhibition of the E3 Ubiquitin-Protein Ligase CBL-B. Org Lett. 24:9468-9472, 2022.; Martinez-Fructuoso, L; Arends, S. J. R.; Freire, V. F.; Evans, J. R.; DeVries, S.; Peyser, B. D.; Akee, R. K.; Thornburg, C. C.; Kumar, R.; Ensel, S.; Morgan, G. M.; McConachie, G. D.; Veeder, N.; Duncan, L. R.; Grkovic, T.; and O'Keefe, B. R. A screen for new antimicrobial natural products from the NCI Program for Natural Product Discovery prefractionated extract library. ACS Infectious Diseases, 2023]. 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. 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 continued a CRADA with Astra Zeneca to screen NPNPD fractions against an oncology target and have completed 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 a grant 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.

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（2022 财年）取得的进展。 1. 2022 财年，NPNPD 达到了 18,000 种土壤真菌的水平，这些真菌经过电镀、拍照和冷冻保存以供长期使用。此外，还进行了410次大规模发酵和提取。 2、完成了1000株海洋放线菌和1000株海洋真菌的基因测序和分类测定（目前正在进行铺板、拍照、冻存以备长期使用）。 3. 预分馏工作生产了 70,000 个馏分，到 2022 年底，生产的总馏分达到 580,000 个。 4. NPNPD 接种了 5,000,000 口馏分井，供应给校外社区。 5. NPNPD 目前已执行 10 项合作协议、2 个 CRADA、5 个 CDA 以及另外 19 个 MTA，用于接收预分馏样本。 6. NPNPD 又收到了 7 个 MTA 在 2022 年接收 NPNPD 分数的请求。 7. 与 NIAID 启动了一项新的机构间协议，并继续与 NCCIH 和 NCATS 签订 IAA。与癌症预防司启动了一项新的联合计划。还与芝加哥伊利诺伊大学启动了新的 CRADA，并与诺华公司签订了合作协议。 8. NPNPD 又向研究实验室运送了 1,900,000 个预分馏样品进行筛查。 9. NPNPD 化学实验室对预分馏样品筛选中鉴定出的生物活性组分进行了 1,386 次二级纯化，并将 30,000 个高度纯化的样品返回筛选中心。 2. 实现倡议和癌症登月目标描述为实现该倡议的目标和成果所取得的主要成就。生产 580,000 个预分馏天然产物样品。已准备好包含 20,000,000 个预分馏样品的 384 孔板，准备运输。向公众发布了首批 500,000 个分数。在执行 50 个 MTA 后，将 7,200,000 个电镀筛查样品运送到校外筛查实验室。生产了 80,000 个在 NPNPD 组分库筛选中鉴定的活性组分的纯化亚组分。创建了包含 24,000 种美国土壤真菌和 6500 种澳大利亚海洋微生物的新微生物库。将技术转让给多个校外研究中心（南非、巴西、韩国、瑞典）。鉴定出一种具有潜在抗癌活性的新型激酶抑制剂，已获得 NCI 的专利。鉴定出一种新型环肽，它是 TDP1 酶的第一个变构抑制剂，已获得 NCI 的专利，并且是与 Genentech 签订合作协议的主题。向弗吉尼亚理工学院和州立大学、哈佛医学院、澳门大学、圣保罗大学（巴西）、NIAID 药物开发兴趣小组、北卡罗来纳大学格林斯伯勒分校、国家补充与综合中心就 NPNPD 进行邀请演讲卫生部门、比勒陀利亚大学、西开普大学、开普敦大学和罗德岛大学（南非）以及国家癌症咨询委员会。发表了 4 篇手稿，其中 3 篇出现在各自期刊的封面上 [Evans JR、Akee RK、Chanana S、McConachie GD、Thornburg CC、Grkovic T、O'Keefe BR。美国国家癌症研究所 (NCI) 天然产物发现计划：利用人工神经网络探索天然产物样品的 NCI-60 筛选数据。 ACS欧米茄。 8(10):9250-9256, 2023; Wilson BAP、Li N、Martinez Fiesco JA、Dalilian M、Wang D、Smith EA、Wamiru A、Shah R、Goncharova EI、Beutler JA、Grkovic T、Zhang P、O'Keefe BR。合成和天然产物腺苷 3',5'-环单磷酸依赖性蛋白激酶 A (PKA) 抑制剂的生化发现、细胞内评估和晶体学表征。 ACS 药理学翻译科学。 6（4）：633-650，2023。； Khong QT, Li D, Wilson BAP, Ranguelova K, Dalilian M, Smith EA, Wamiru A, Goncharova EI, Grkovic T, Voeller D, Lipkowitz S, Schnermann MJ, O'Keefe BR, Du L. Plakinidine B 引线的光化学二聚化有效抑制 E3 泛素蛋白连接酶 CBL-B。奥格·莱特。 2022 年 24:9468-9472。；马丁内斯-果果，L；阿伦兹，S.J.R.；弗莱雷，V.F.；埃文斯，J.R.；德弗里斯，S.；佩瑟，B.D.；阿基，R.K.；桑堡，C.C.；库马尔，R.；恩塞尔，S.；摩根，GM；麦科纳奇，G.D.；维德，N.；邓肯，L.R.；格尔科维奇，T.；和 O'Keefe, B. R. 从 NCI 天然产物发现预分级提取物库计划中筛选新的抗菌天然产物。 ACS 传染病，2023 年]。 b.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。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，我们继续与阿斯利康 (Astra Zeneca) 合作开展 CRADA，针对肿瘤学目标筛选 NPNPD 分数，并与诺华 (Novartis) 完成了 CDA。 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 RFA 来收集海洋藏品，NCCIH 为全球天然产物 NMR 数据库提供了拨款。我们还与 NCI 癌症预防部门启动了一项联合计划，该部门将资助使用 NPNPD 分数的筛查项目。

项目成果

National Cancer Institute (NCI) Program for Natural Product Discovery: Exploring NCI-60 Screening Data of Natural Product Samples with Artificial Neural Networks.

美国国家癌症研究所 (NCI) 天然产物发现计划：利用人工神经网络探索天然产物样品的 NCI-60 筛选数据。

• 发表时间: 2023-03-14
• 影响因子: 4.1
• 作者: Evans, Jason R;Akee, Rhone K;Chanana, Shaurya;McConachie, Grant D;Thornburg, Christopher C;Grkovic, Tanja;O'Keefe, Barry R
• 通讯作者: O'Keefe, Barry R

Screen for New Antimicrobial Natural Products from the NCI Program for Natural Product Discovery Prefractionated Extract Library.

从 NCI 天然产物发现预分级提取物库计划中筛选新的抗菌天然产物。

• 发表时间: 2023-06-09
• 影响因子: 5.3
• 作者: Martínez;Arends, S J Ryan;Freire, Vitor F;Evans, Jason R;DeVries, Sean;Peyser, Brian D;Akee, Rhone K;Thornburg, Christopher C;Kumar, Rohitesh;Ensel, Susan;Morgan, Gina M;McConachie, Grant D;Veeder, Nathan;Duncan, Leonard R
• 通讯作者: Duncan, Leonard R

The NCI library of traditional Chinese medicinal plant extracts - Preliminary assessment of the NCI-60 activity and chemical profiling of selected species.

• DOI: 10.1016/j.fitote.2019.104285
• 发表时间: 2019-09-01
• 期刊: Fitoterapia
• 影响因子: 3.4
• 作者: M. He;T. Grkovic;Jason R. Evans;C. Thornburg;R. Akee;J. Thompson;J. Whitt;Matthew J Harris
• 通讯作者: Matthew J Harris

Molecular genomic features associated with in vitro response of the NCI-60 cancer cell line panel to natural products.

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。

• 发表时间: 2021-02
• 影响因子: 6.6
• 作者: Krushkal, Julia;Negi, Simarjeet;Yee, Laura M;Evans, Jason R;Grkovic, Tanja;Palmisano, Alida;Fang, Jianwen;Sankaran, Hari;McShane, Lisa M;Zhao, Yingdong;O'Keefe, Barry R
• 通讯作者: O'Keefe, Barry R

Erythrofordins D and E, two new cassaine-type diterpenes from Erythrophleum suaveolens.

Erythrofordins D 和 E，是来自 Erythrophleum suaveolens 的两种新的木薯碱型二萜。

• 发表时间: 2019
• 影响因子: 2.7
• 作者: Grkovic, Tanja;Evans, Jason R;Akee, Rhone K;Guo, Liang;Davis, Myrtle;Jato, Johnson;Grothaus, Paul G;Ahalt;Hollingshead, Melinda;Collins, Jerry M;Newman, David J;O'Keefe, Barry R
• 通讯作者: O'Keefe, Barry R