NCI Program for Natural Products Discovery - Cures

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

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*