NCI Program for Natural Products Discovery - Cures

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Specific Aims and Current Status of Efforts to Achieve those Aims Aim 1. Create new technologies to build an enhanced NP pre-fractionated library amenable to modern high-throughput targeted screening programs. - The NPNPD has created a new high-throughput natural product chemistry laboratory at the NCI at Frederick campus including jointly-developed robotic systems for pre-fractionation, weighing, plating fractions, and storing the fraction library. - The NPNPD has so far pre-fractionated >90,000 crude natural product extracts, produced >680,000 pre-fractionated natural product samples, and released 500,000 samples to the public. Additional pre-fractionated samples will be released in Q1 2025. - The NPNPD has plated >30,000,000 wells of pre-fractionated samples into 384-well plates for release to the public (>1800 unique, 384-well plates, 35-50 replicates each). - The NPNPD has engaged in outreach to the extramural community to aid other programs to adapt NPNPD technologies including labs in Brazil, S. Africa, S. Korea, Sweden, Germany, and the United States (VA, MS, MI, CA). - The NPNPD has worked with commercial analytics companies (Bruker, Gilson, ACD Labs, MesrReNova, Perkin Elmer, etc.) to optimize commercially available software to enable automated high throughput natural products chemistry programs. Thornburg CC, et al. NCI Program for Natural Product Discovery: A Publicly-Accessible Library of Natural Product Fractions for High-Throughput Screening. ACS Chem Biol. 13(9):2484-2497, 2018. (>5000 downloads, 80 citations) Hanna GS, et al. Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses. J Nat Prod. 84(11):3001-3007, 2021. Aim 2. Expand the chemical diversity available to the public from culturable microorganisms with new methods and libraries. - The NPNPD has obtained a library of >24,000 non-duplicate (by sequence) soil fungi from the United States and an additional >6000 marine microbes from Australia. - The NPNPD has sequenced ~1200 Australian marine actinomycete specimens include whole-genome sequencing on 20 unique organisms. We have also completed taxonomic ITS sequencing of >1200 Australian marine fungi. - The NPNPD has performed >3,000 large-scale fungal fermentations and extractions. Thornburg CC, et al. National Cancer Institute (NCI) Program for Natural Product Discovery: Creation of A Diverse Fungal Extract Library for High-Throughput Screening. (submitted) Aim 3. Provide the pre-fractionated library to screening centers worldwide to accelerate drug discovery. - The NPNPD has executed >80 Material Transfer Agreements since the pre-fractionated library became available in 2019 (>1 per month, Appendix A). - In addition, the NPNPD has received another 30 requests for MTAs that have not yet been executed. - To date, the NPNPD has shipped >9,500,000 samples to the research community since the first release of pre-fractionated extracts in 2019. - The NPNPD has executed 25 collaboration agreements including those with NIAID, NCATS, NCCIH, NIDCR, WRAIR, Astra Zeneca, Genentech, and Novartis. Aim 4. Provide high throughput screening support for researchers to enable targeted discovery efforts. - The NPNPD has worked closely with both intramural and extramural researchers to productively screen NPNPD fraction libraries and identify novel anticancer compounds. - The NPNPD has worked with NCATS, NCCIH, and extramural research groups to enable funding of screens of the NPNPD fraction libraries against NIH HEAL Initiative targets. - The NPNPD worked with NIAID on a screen of >320,000 fractions for antimicrobial activity. - The NPNPD is working with numerous extramural researchers on projects to identify potential anticancer agents including: - Modulators of the stability of beta-catenin (with William Kaelin, Harvard) - Selective cytotoxic terpenoids that shrink tumors in initial mouse studies (with Debananda Pati, Baylor College of Med. - Natural products that induce degradation of CARM1 (Tim Bugni, Univ. Wisconsin) -multiple projects in the MTP/CCR/NCI