Expanding the Target Landscape by Drugging the Undruggable (R21 Clinical Trial Not Allowed) | PAR 25 442

FAQs: NIH PAR-25-442 - Expanding the Target Landscape by Drugging the Undruggable (R21 Clinical Trial Not Allowed)

What is the purpose of NIH PAR-25-442?

This funding opportunity supports exploratory, early-stage research aimed at expanding what drug discovery can realistically target. The focus is on disease-relevant biological targets that have historically been considered "undruggable," especially in intractable human diseases where existing approaches are limited, ineffective, or absent.

What activity code/mechanism is this opportunity using?

This is an NIH R21 mechanism, which is intended for exploratory and developmental research. It is generally suited for higher-risk, early proof-of-concept ideas rather than mature translational programs.

Are clinical trials allowed under this NOFO?

No. Clinical trials are not allowed. Proposed work must remain preclinical and should not include human clinical trial activities.

What kind of scientific projects does this NOFO encourage?

The NOFO encourages bold, innovative projects that demonstrate new strategies for selectively modulating a previously hard-to-target class of biological targets. The emphasis is on approaches that could shift the boundaries of what is considered reachable by drug discovery, rather than incremental work using conventional modalities.

What is meant by an "undruggable target class" in this opportunity?

Applicants are expected to define a coherent target class (not just a single target) that is tied to a human disease area and explain why established therapeutic approaches have struggled to address it. The project should then propose a credible method or agent to selectively modulate one or more members of that class.

Do applicants need to focus on a single target or a class of targets?

The core expectation described here is to pick and justify an "undruggable target class." While the research may involve one or more members of that class, the application should be framed around the broader class and why it represents an inaccessible landscape for typical drug discovery.

What does "selectively modulate" mean in the context of this NOFO?

The project should aim to engage or affect targets within the chosen class with specificity, rather than causing broad, non-specific perturbation. A strong application typically includes a plan to test selectivity and demonstrate target engagement or functional modulation in a way that supports the claim of selective action.

What types of strategies or approaches are appropriate to propose?

Based on the description provided, appropriate approaches may include developing a new method or an agent to modulate the class using innovative concepts such as new chemistry, binding or degradation strategies, delivery-enabling platforms, screening approaches, validation methods, or other inventive ways to achieve selective modulation.

How much preliminary data is expected for an R21 application under this program?

R21 projects are oriented toward exploratory ideas that may not have extensive preliminary data, as long as the proposal is supported by a strong rationale and a feasible plan to generate proof-of-concept evidence.

What kinds of outcomes is NIH looking for in a strong application?

The NOFO emphasizes early, compelling evidence that a previously inaccessible target landscape can be approached with specificity and a path toward further development. Strong proposals typically present a clear "if this works, it changes the game" premise and practical experiments/milestones to demonstrate selectivity, target engagement or functional modulation, and feasibility.

What kinds of research activities fit within the "preclinical only" boundary?

Examples mentioned or implied include assay development, computational and experimental discovery workflows, development of chemical or biologic tools, mechanistic studies, and early efficacy signals in relevant models. The goal is enabling science and early validation, not human testing.

Does this NOFO support late-stage translational development?

The description emphasizes exploratory, early-stage proof-of-concept work rather than mature translational programs. The intended output is enabling data and validation that could support future development under other mechanisms.

Who is eligible to apply?

Eligibility is broad across the U.S. research ecosystem. Eligible applicants include various U.S. government entities (state, county, city/township, special district), public and independent school districts, public housing authorities/Indian housing authorities, federally recognized tribal governments, and tribal organizations that are not federally recognized. Eligible organizations also include public/state-controlled and private institutions of higher education, nonprofits (501(c)(3) and non-501(c)(3), excluding institutions of higher education in those nonprofit categories), for-profit organizations that are not small businesses, and small businesses.

Are any specific institution types explicitly highlighted as eligible?

Yes. The opportunity explicitly calls out eligibility for Alaska Native and Native Hawaiian Serving Institutions; Asian American Native American Pacific Islander Serving Institutions (AANAPISIs); Hispanic-serving Institutions; Historically Black Colleges and Universities (HBCUs); Tribally Controlled Colleges and Universities (TCCUs); faith-based or community-based organizations; regional organizations; eligible federal agencies; and U.S. territories or possessions.

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

No. Non-U.S. entities are not eligible to apply.

Can a U.S. organization include a non-U.S. component in the application?

No. Non-U.S. components of U.S. organizations are not eligible, and foreign components (as NIH defines them) are not allowed.

What is the opportunity number and title?

The opportunity is titled "Expanding the Target Landscape by Drugging the Undruggable (R21 Clinical Trial Not Allowed)" and the NOFO number is PAR-25-442.

What is the funding category and agency?

This is an NIH discretionary grant opportunity within the health funding category.

Which CFDA numbers are associated with this opportunity?

The opportunity is associated with multiple CFDA numbers: 93.121, 93.242, 93.350, 93.855, and 93.867.

When was this opportunity created?

The opportunity was created on 2025-06-17.

What is the listed closing date?

The listed original closing date is 2028-02-17, indicating a multi-year window in which applications may be accepted according to the NOFO's submission schedule.

Does the excerpt specify an award ceiling or the expected number of awards?

No. The excerpt does not list an award ceiling or an expected number of awards.

Where should applicants look for budget expectations, receipt dates, and review details?

Because these details are not included in the excerpt, applicants would need to consult the full NOFO text and any related NIH Guide notices for budget expectations, application receipt dates, review criteria, and any institute-specific interests or priorities.

What is a common pitfall this NOFO is trying to avoid?

The description suggests reviewers will look for genuine novelty and specificity rather than general perturbation. A common pitfall would be proposing an approach that does not credibly demonstrate selective modulation of the target class or that drifts into clinical trial territory.

How should a proposal connect the science to human disease?

The chosen undruggable target class should be clearly tied to a human disease area. The project should explain why the class matters for disease and why it has been difficult to drug with established therapeutic types, then show a testable plan for selective modulation.