Expanding the Target Landscape by Drugging the Undruggable (R21 Clinical Trial Not Allowed)
🏛 National Institutes of Health (HHS-NIH11)
✓ Free, no account · Source: Grants.gov · Last verified Jul 27, 2026
Can you apply?
This grant is for biomedical and behavioral research organizations seeking to expand therapeutic targets for diseases currently considered "undruggable." It supports early-stage exploratory projects focused on novel approaches to drug discovery and target validation for proteins, pathways, or conditions that have resisted conventional therapeutic intervention. Eligible recipients include nonprofit research institutions, academic medical centers, independent research organizations, small businesses, and faith-based organizations that have federal research capabilities. The program supports U.S.-based research and prioritizes innovative methodologies to overcome current drug development barriers. Clinical trials are explicitly not allowed under this funding mechanism.
Not the right fit? Find grants for your organization in 5 questions →
Program description
The purpose of this Notice of Funding Opportunity (NOFO) is to solicit applications for exploratory and early-stage projects that focus on undruggable target classes within intractable human disease. Applicants will identify a human disease relevant undruggable target class and develop a method or agent that is selective for one or more targets within that target class. This NOFO is intended to jumpstart research that demonstrates innovative strategies to modulate targets that cannot be addressed by established therapeutic types, furthering the development of methods and/or agents selective for undruggable target classes.
Who can apply
Eligible applicants
How to apply
Application links
Required documents
- SF-424 (Application for Federal Assistance)
- Project Narrative (typically 6–12 pages describing scientific rationale, innovation, and methods)
- Detailed Budget and Budget Justification
- Biographical sketches of key personnel (NIH format, 5 pages max per person)
- Support Letters from collaborating institutions (if applicable)
- Data Management and Sharing Plan
- Conflict of Interest disclosure
- Vertebrate Animals or Human Subjects sections (if applicable, though clinical trials are not allowed)
Program contact
- 👤 National Institutes of Health
- 📧 grantsinfo@nih.gov
- 📞 301-402-2541
Funding track record
Recent awards under CFDA 93.350 from the last 3 years — real organizations that won funding through this same program.
Top 10 Largest Recent Awards
-
$139,753,636
-
$118,592,298
-
$118,098,707
-
$112,138,469
-
$102,903,347
-
$102,422,256
-
$100,095,982
-
$99,978,264
-
$98,955,036
-
$97,784,066
Top States by Funding
- CA 13 awards $662.0M
- NY 11 awards $506.1M
- MA 6 awards $321.4M
- NC 5 awards $313.7M
- OH 5 awards $167.6M
Source: USAspending.gov — federal spending transparency. Data covers last 3 years.
Funding history
Annual funding for this program — Federal obligations (CFDA 93.350). How funding has trended year over year.
| 2024 | $595,597,945 | |
| 2025 | $626,227,752 |
FAQ
Who can apply for this R21 grant?
Nonprofit research institutions, academic centers, small businesses, independent research organizations, and faith-based entities with research infrastructure are eligible. Foreign entities may participate as collaborative partners but cannot be lead applicants.
What is the application deadline?
Applications are typically due on the fixed deadline of February 17, 2028. The application window opens June 17, 2025, so plan to submit well before the deadline.
What types of research activities are supported?
The R21 mechanism supports exploratory, early-stage research to validate novel drug targets or develop new therapeutic approaches for undruggable diseases. Clinical trials are not permitted under this funding mechanism.
How competitive is this grant?
R21 grants are moderately competitive. Success depends on demonstrating scientific novelty, a clear mechanistic understanding of your undruggable target, preliminary data supporting feasibility, and realistic timelines for an early-stage project.
What is the typical funding range?
R21 grants typically provide $275,000–$450,000 total costs over 2 years, though amounts vary. Check the NIH announcement for specific budget guidelines and budget caps.
💡 Tips for applicants
- Clearly articulate why your target is considered "undruggable" and what novel approach you propose to overcome existing barriers. Use this as your competitive advantage.
- Include preliminary data demonstrating proof-of-concept for your novel approach, even if preliminary. NIH reviewers want evidence of feasibility before funding exploratory work.
- Remember that clinical trials are not allowed; frame your project as target validation, assay development, or mechanism-of-action research rather than patient-facing studies.
- Build a strong, focused team with complementary expertise in drug discovery, target biology, and your specific therapeutic area. Highlight each investigator's relevant publications and prior success with high-risk projects.
- Use the R21 timeline (typically 2 years) strategically. Propose discrete, achievable milestones that will generate data publishable or suitable for future R01 grant applications.
⚠️ Common mistakes
Applicants often underestimate the novelty bar for R21 grants—simply applying existing methods to a new protein is unlikely to succeed. Another frequent mistake is including clinical trial components or preliminary human data, which violates the program's restrictions. Finally, many proposals lack sufficient preliminary data to convince reviewers that the "undruggable" target can actually be tackled within the 2-year funding period; weak feasibility evidence is a leading rejection reason.
Similar grants
- OPEN Expanding the Therapeutic Pipeline for Treating and Preventing Alzheimer’s Disease and Related Dementias: Preclinical Validation and Drug Discovery for Novel Candidate Targets (U01 Clinical Trial Not — National Institutes of Health
- OPEN Preclinical Proof of Concept Studies for Rare Diseases (R21 Clinical Trial Not Allowed) — National Institutes of Health
- OPEN Assay development and screening for discovery of chemical probes, drugs or immunomodulators (R01 Clinical Trial Not Allowed) — National Institutes of Health
- OPEN Advanced Development and Validation of Emerging Technologies for Basic and Clinical Cancer Research (R33 Clinical Trial Not Allowed) — National Institutes of Health
- OPEN Ancillary Studies to Ongoing Clinical Projects (RP1 Clinical Trial Not Allowed) — National Institutes of Health