NCI Program for Natural Products Discovery - Cures

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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.