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

Opportunity Information: Apply for PAR 25 442

The NIH funding opportunity "Expanding the Target Landscape by Drugging the Undruggable (R21 Clinical Trial Not Allowed)" (PAR-25-442) is designed to spark exploratory, early-stage research that tackles one of the toughest bottlenecks in therapeutics: disease-relevant biological targets that have historically been considered "undruggable." The central idea is to move beyond conventional therapeutic modalities and open up new classes of targets for intervention in intractable human diseases, meaning conditions where existing approaches are limited, ineffective, or do not exist. This NOFO specifically encourages projects that are bold and innovative, with an emphasis on demonstrating new strategies that could shift what is considered reachable by drug discovery.

At the core of an application is the requirement to pick an "undruggable target class" that is clearly tied to a human disease area and then develop either a method or an agent that can selectively modulate one or more members of that class. In practice, this means applicants are expected to define a coherent target class (not just a single target) and justify why it has been difficult to address using established therapeutic types. The work should then show a credible, testable approach for selectively engaging targets within that class, whether through a new chemistry concept, a new binding or degradation strategy, a novel delivery-enabling platform, a new screening or validation method, or another inventive way to achieve selective modulation. The emphasis is on jumpstarting a line of research: producing compelling early evidence that a previously inaccessible landscape can be approached with specificity and a path toward further development.

Because this is an R21 mechanism, the program is oriented toward exploratory and developmental efforts rather than mature translational programs. R21 projects are generally expected to take on higher-risk ideas that may not yet have extensive preliminary data, but that are grounded in a strong rationale and a feasible plan to generate proof-of-concept results. In that spirit, successful proposals typically articulate a clear "if this works, it changes the game" premise, paired with practical milestones showing how the team will test selectivity, demonstrate target engagement or functional modulation, and establish that the approach is more than a general perturbation. While the NOFO does not provide detailed scientific constraints in the excerpt provided, the stated purpose makes it clear that reviewers will be looking for genuine novelty relative to standard therapeutic approaches and for a convincing argument that the proposed strategy can reach targets previously out of bounds.

Clinical trials are not allowed under this opportunity, which means the proposed research must stay on the preclinical side. Applicants can generally focus on assay development, computational and experimental discovery workflows, development of chemical or biologic tools, mechanistic studies, early efficacy signals in relevant models, and other preclinical demonstrations that support the feasibility of modulating an undruggable target class. The goal is not to run human studies, but to establish enabling science and early validation that can support future, more advanced translational work under other mechanisms.

Eligibility is broad across the U.S. research ecosystem. Eligible applicants include a wide range of government entities (state, county, city or township governments, special district governments), public and independent school districts, public housing authorities/Indian housing authorities, federally recognized tribal governments, and tribal organizations that are not federally recognized. Academic eligibility includes public and state-controlled institutions of higher education as well as private institutions of higher education. The NOFO is also open to nonprofits (both 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. It also explicitly calls out additional eligible applicant types such as 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. On the other hand, foreign participation is restricted: non-U.S. entities are not eligible to apply, non-U.S. components of U.S. organizations are not eligible, and foreign components (as NIH defines them) are not allowed.

Administratively, this is a discretionary NIH grant opportunity within the health funding category and is associated with multiple CFDA numbers (93.121, 93.242, 93.350, 93.855, 93.867), reflecting that it may align with several NIH institutes or program areas. The opportunity was created on 2025-06-17, and the listed original closing date is 2028-02-17, indicating a multi-year window during which applications may be accepted according to the NOFO's submission schedule. The excerpt does not list an award ceiling or expected number of awards, so applicants would need to consult the full NOFO text (and any related NIH guide notices) for budget expectations, receipt dates, review criteria details, and any institute-specific interests or scientific priorities tied to this program.

Overall, PAR-25-442 is best read as an invitation to bring forward creative, early evidence that a previously inaccessible target class in a real human disease context can be selectively modulated in a way that could ultimately expand the therapeutic toolbox. The strongest projects will usually be those that define the undruggable problem precisely, propose a genuinely differentiated strategy, and lay out a tight set of experiments that can convincingly demonstrate selectivity and functional impact without drifting into clinical trial territory.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Expanding the Target Landscape by Drugging the Undruggable (R21 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): 93.121, 93.242, 93.350, 93.855, 93.867.
• This funding opportunity was created on 2025-06-17.
• Applicants must submit their applications by 2028-02-17.
• 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 25 442

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