The National Cancer Institute (NCI) has announced a funding opportunity for the “Discovery and Development of Natural Products for Cancer Interception and Prevention” through a UG3/UH3 phased cooperative agreement. This program aims to support the discovery and preclinical development of natural products as cancer prevention agents, focusing on compounds with favorable safety and non-toxic profiles. The UG3 phase will support up to three years of initial research, including target selection, clinical sample verification, and assay validation. If these milestones are achieved, projects may progress to a UH3 phase, which involves large-scale high-throughput screening (HTS), detailed efficacy and toxicity studies, and dose optimization, supported by an additional two years of funding.

Natural products are uniquely suited for drug discovery due to their structural and functional diversity, with only a fraction of them explored for therapeutic potential. NCI’s Natural Product Discovery Program offers a vast pre-fractionated library of natural compounds, available for screening as part of this program. The HTS assays must meet rigorous standards, and applicants are encouraged to leverage NCI and NIH resources, such as the NCATS for HTS. High-throughput compatible assays will screen natural products for cancer interception pathways, and promising results may advance to medicinal chemistry for compound optimization and larger-scale testing. The program also encourages applying new technologies and methods to improve assay sensitivity and reliability.

The UG3 phase will involve preparatory activities essential for the UH3 phase, such as selecting and validating cancer-interception targets, developing prototype HTS-compatible assays, and conducting pilot screens using commercial or NCI-provided libraries. Successful projects that meet milestones in this phase will transition to the UH3 phase, which encompasses a full-scale HTS campaign, comprehensive lead characterization, pharmacokinetics, and in vivo efficacy testing. The ultimate goal is to identify natural product agents with promising in vivo efficacy and minimal toxicity, which could be further developed within NCI’s PREVENT Cancer Prevention Program pipeline.

Eligible applicants include a broad range of U.S.-based higher education institutions, nonprofits, and for-profit organizations, but foreign organizations are excluded. Applicants must ensure all necessary registrations, including SAM, Grants.gov, and eRA Commons, are complete before submission. The application budget for the UG3 phase is capped at $250,000 in direct costs annually, with the UH3 phase budget capped at $400,000 per year. The entire award duration across both phases is capped at five years, subject to administrative review and satisfactory progress at the end of the UG3 phase.

Applications must clearly outline milestones and timelines, with well-defined criteria for assessing success at each stage, especially the transition between phases. The NCI program staff will work collaboratively with awardees throughout the project, providing scientific guidance, technical resources, and support for screening and isolation of bioactive compounds. Applicants are encouraged to consult with NCI staff before submission to clarify project scope and resources, particularly if seeking NCATS support, which requires a formal letter of collaboration from NCATS leadership.

All applications are due by 5:00 PM local time on June 13, 2025, and late submissions will not be accepted. The first project period could start as early as April 2026 following administrative and peer reviews. This funding opportunity is expected to award up to 12 projects, with $4.5 million allocated for the period of FY2024-FY2026.