Assay development and screening for discovery of chemical probes, drugs or immunomodulators (R01 Clinical Trial Not Allowed) | PAR 23 264

Opportunity Information: Apply for PAR 23 264

The NIH National Cancer Institute funding opportunity PAR 23-264 is an R01 grant that supports early-stage discovery research aimed at finding small molecules that can either serve as chemical probes to better understand disease biology or act as drug-like modulators (agonists or antagonists) of specific disease-relevant targets, including targets tied to therapy and immunotherapy. The program is focused on generating credible, well-characterized small-molecule "hits" that are validated and relevant to health outcomes aligned with the missions of the participating NIH Institutes. Because it is labeled "Clinical Trial Not Allowed," the work is expected to remain in the preclinical discovery and early translational space rather than involving human subject clinical trials.

The scope is intentionally broad across the small-molecule discovery pipeline, but it is centered on assay-driven screening and the practical steps needed to move from a biological idea to compounds with real value for research or future therapeutic development. The first major stage it supports is assay development, meaning applicants can propose building and optimizing robust assays around a defined biological target, pathway, or disease mechanism. These assays should be suitable for screening and designed with the goal of finding compounds that can be used as research probes to illuminate target function, confirm or uncover disease mechanisms, and potentially provide starting points for drug discovery.

After assay development, the NOFO supports implementing screening campaigns to identify initial hits. This can include high-throughput, target-focused screening (typical of large compound libraries and automated workflows) as well as moderate-throughput approaches such as phenotypic screens (where the readout is a cellular or organismal phenotype rather than direct binding to a target) and fragment-based screening (where smaller chemical fragments are screened and later elaborated). The emphasis is on thoughtfully designed screening strategies that match the biology and the practical realities of hit identification.

A substantial portion of the opportunity is aimed at hit validation, which is where many screening projects succeed or fail. Applicants are encouraged to plan for secondary confirmation work, including orthogonal assays that use a different assay format or detection method to rule out artifacts and false positives. The NOFO also calls out advanced cheminformatics analysis, which typically involves clustering hits by chemotype, identifying problematic substructures, evaluating novelty, and prioritizing compounds for follow-up. In addition, it highlights early medicinal chemistry inspection to triage and prioritize the hit set, plus follow-up experiments to understand a compound's mode of action and mechanism of action. In practice, that means showing that the hit behaves consistently, engages the intended biology, and has enough supporting evidence to justify additional investment.

The final stage supported is hit-to-lead optimization, which goes beyond simply confirming activity and into improving compound quality. This includes structure-activity relationship (SAR) work to optimize potency, target engagement, and selectivity, while reducing chemical liabilities that could limit usefulness as a probe or future lead. The NOFO also explicitly includes typical early drug-discovery property work such as ADME (absorption, distribution, metabolism, and excretion) evaluation, along with pharmacokinetic (PK) and pharmacodynamic (PD) studies. When appropriate, applicants may include in vivo modeling to test biological effects or efficacy in relevant preclinical models, as long as the work stays within non-clinical boundaries.

From an eligibility standpoint, the program is open to a wide range of applicant types. In addition to standard academic and nonprofit research organizations, eligible applicants include for-profit organizations (other than small businesses) and small businesses, as well as multiple levels of government entities (state, county, city/township, special districts) and independent school districts. The opportunity also highlights inclusion of institutions and organizations that are sometimes specifically encouraged in NIH programs, such as Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Tribally Controlled Colleges and Universities, Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions. Non-U.S. entities (foreign organizations), U.S. territories or possessions, faith-based or community-based organizations, and certain tribal governments and regional organizations are also listed as eligible, which signals broad openness to diverse organizational structures and geographic locations.

Administratively, this is a discretionary grant opportunity offered by the National Institutes of Health under CFDA 93.395, with the National Cancer Institute as the named institute leading the solicitation. The original closing date provided is September 7, 2026. An award ceiling is not specified in the provided source details, and the expected number of awards is not listed, which typically means applicants should rely on the full NOFO text and NIH standard R01 budgeting and review expectations when planning project scale and costs.

Overall, the opportunity is designed for teams that can connect strong biological rationale with credible assay development and screening execution, and then follow through with the validation and chemistry needed to produce high-confidence, well-understood small molecules. The most competitive projects are likely to be those that show a clear path from assay to hits to validated, prioritized compounds, with a realistic plan for de-risking artifacts, demonstrating mechanism, and improving compound properties enough for the resulting molecules to be genuinely useful as probes and/or as pre-therapeutic leads for future development.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Assay development and screening for discovery of chemical probes, drugs or immunomodulators (R01 Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.395.
• This funding opportunity was created on 2023-08-10.
• Applicants must submit their applications by 2026-09-07. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

Apply for PAR 23 264

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