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

FAQs: NIH NCI PAR 23-264 (R01) Early-Stage Small-Molecule Discovery (Clinical Trial Not Allowed)

1) What is PAR 23-264?

PAR 23-264 is a National Institutes of Health (NIH) National Cancer Institute (NCI) funding opportunity for an R01 research grant supporting early-stage discovery research focused on small-molecule discovery and optimization.

2) What is the main goal of this funding opportunity?

The goal is to generate credible, well-characterized small-molecule "hits" that can serve as chemical probes to understand disease biology and/or as drug-like modulators (agonists or antagonists) of disease-relevant targets, including targets tied to therapy and immunotherapy. The work should be relevant to health outcomes aligned with the missions of participating NIH Institutes.

3) What types of molecules does the program focus on?

The program focuses on small molecules, specifically aiming to identify and validate compounds that are credible hits and, where appropriate, can be advanced through hit-to-lead optimization to improve their usefulness as probes or starting points for future therapeutic development.

4) Does this opportunity support chemical probes as an endpoint?

Yes. A central purpose is to discover small molecules that can function as chemical probes to illuminate target function, confirm or uncover disease mechanisms, and deepen understanding of disease biology.

5) Does the opportunity support drug discovery efforts?

Yes, in the early discovery and early translational sense. It supports identifying drug-like modulators and improving them through hit-to-lead work (for example SAR, selectivity, and early property assessment) to create strong starting points for later development.

6) What does "Clinical Trial Not Allowed" mean in this NOFO?

It means the proposed research is expected to remain in preclinical discovery and early translational space and should not involve human subject clinical trials.

7) What stages of the small-molecule discovery pipeline are within scope?

The scope is broad but centered on assay-driven discovery and the practical steps needed to move from a biological idea to compounds with real research or future therapeutic value. It includes assay development, screening, hit validation, and hit-to-lead optimization.

8) Is assay development an allowable and supported activity?

Yes. Applicants may propose building and optimizing robust assays around a defined biological target, pathway, or disease mechanism. The assays should be designed to support screening and hit identification.

9) What kinds of assays are expected?

The opportunity emphasizes robust, screening-suitable assays tied to a defined biological rationale (target, pathway, or mechanism). The details of assay format are not constrained in the provided description, but the intent is that assays should reliably support discovery and validation workflows.

10) What kinds of screening approaches are supported?

The NOFO supports implementing screening campaigns to identify initial hits, including:

• High-throughput, target-focused screening (large libraries and automation)
• Moderate-throughput approaches such as phenotypic screening (cellular or organismal phenotype readouts)
• Fragment-based screening (screening small chemical fragments for later elaboration)

11) Is phenotypic screening allowed even if it is not target-binding focused?

Yes. Phenotypic screens are explicitly included as a supported moderate-throughput approach, where the readout is a phenotype rather than direct binding to a specific target.

12) Is fragment-based screening within scope?

Yes. Fragment-based screening is explicitly listed as an included screening approach.

13) What is the program's emphasis regarding screening strategy?

The emphasis is on thoughtfully designed screening strategies that match the biology and the practical realities of identifying true hits.

14) How important is hit validation in this opportunity?

Hit validation is a major focus. The program highlights that many screening projects succeed or fail at this stage and encourages thorough confirmation and follow-up to produce high-confidence, well-understood hits.

15) What kinds of hit validation activities are encouraged?

The opportunity encourages secondary confirmation work, including:

• Orthogonal assays using different formats or detection methods to rule out artifacts and false positives
• Follow-up experiments to understand mode of action and mechanism of action
• Planning that demonstrates consistent behavior and engagement with the intended biology

16) What is meant by orthogonal assays in this context?

Orthogonal assays refer to confirmation assays that use a different assay format or detection method than the primary screen, helping rule out assay artifacts and false positives.

17) Does the NOFO mention cheminformatics, and how is it used?

Yes. The NOFO highlights advanced cheminformatics analysis, which typically includes clustering hits by chemotype, identifying problematic substructures, evaluating novelty, and prioritizing compounds for follow-up.

18) Is medicinal chemistry work allowed at the hit stage?

Yes. The opportunity calls out early medicinal chemistry inspection to triage and prioritize hit sets, supporting decisions about which compounds to advance.

19) What does "hit-to-lead optimization" cover under this program?

Hit-to-lead optimization includes improving compound quality beyond initial confirmation. This includes structure-activity relationship (SAR) work to improve potency, target engagement, and selectivity, and to reduce chemical liabilities that could limit probe utility or future lead potential.

20) Are ADME studies allowed?

Yes. The NOFO explicitly includes ADME (absorption, distribution, metabolism, and excretion) evaluation as part of early drug-discovery property work.

21) Are PK/PD studies allowed?

Yes. Pharmacokinetic (PK) and pharmacodynamic (PD) studies are explicitly included as allowable components when appropriate.

22) Is in vivo preclinical work allowed?

Yes. 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.

23) Who is the sponsoring agency and lead institute for this opportunity?

The sponsoring agency is the National Institutes of Health (NIH), and the named lead institute is the National Cancer Institute (NCI).

24) What grant mechanism is used?

This opportunity uses the NIH R01 research project grant mechanism.

25) What is the CFDA number associated with this opportunity?

The opportunity is listed under CFDA 93.395.

26) What is the application deadline listed in the provided information?

The original closing date provided is September 7, 2026.

27) Is there an award ceiling specified?

No. An award ceiling is not specified in the provided source details.

28) Is the expected number of awards provided?

No. The expected number of awards is not listed in the provided information.

29) What types of organizations are eligible to apply?

The program is open to a wide range of applicant types, including academic and nonprofit research organizations, for-profit organizations (other than small businesses), and small businesses.

30) Are government entities eligible applicants?

Yes. Multiple levels of government entities are listed as eligible, including state, county, city/township, special districts, and independent school districts.

31) Are minority-serving institutions specifically mentioned as eligible or encouraged?

Yes. The opportunity highlights inclusion of institutions 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.

32) Are non-U.S. (foreign) organizations eligible?

Yes. Non-U.S. entities (foreign organizations) are listed as eligible in the provided description.

33) Are U.S. territories or possessions eligible?

Yes. U.S. territories or possessions are listed among eligible applicants.

34) Are faith-based or community-based organizations eligible?

Yes. Faith-based or community-based organizations are listed as eligible.

35) Are tribal governments and regional organizations eligible?

Yes. Certain tribal governments and regional organizations are listed as eligible.

36) What kinds of projects are likely to be most competitive based on the description provided?

The most competitive projects are likely to connect strong biological rationale with credible assay development and screening execution, then follow through with validation and chemistry to produce high-confidence, well-understood small molecules. Strong applications typically show a clear path from assay to hits to validated, prioritized compounds, with a realistic plan to de-risk artifacts, demonstrate mechanism, and improve compound properties.

37) What is the expected endpoint of the funded work?

The described endpoint is the generation of credible, well-characterized, validated small-molecule hits and, where proposed, improved compounds through hit-to-lead optimization that are genuinely useful as probes and/or as pre-therapeutic leads for future development.

38) Does the opportunity specify a particular disease area?

The description emphasizes disease-relevant targets including those tied to therapy and immunotherapy, and it is led by NCI. Beyond that, the scope is described as intentionally broad within small-molecule discovery, with alignment to the missions of participating NIH Institutes.

39) Does the provided information describe standard budgeting expectations?

It notes that because an award ceiling and number of awards are not listed in the provided details, applicants typically rely on the full NOFO text and NIH standard R01 budgeting and review expectations when planning project scale and costs.

40) What does "assay-driven screening" mean in the context of this program?

In this context, it means discovery efforts centered on developing or using assays suitable for screening compounds, then using those assays to identify hits, confirm them through validation steps, and advance them through chemistry and early property evaluation.