Expanding the Target Landscape by Drugging the Undruggable (R21 Clinical Trial Not Allowed)

The Department of Health and Human Services (HHS), through the National Institutes of Health (NIH), is offering a grant titled “Expanding the Target Landscape by Drugging the Undruggable (R21 Clinical Trial Not Allowed)” under Funding Opportunity Number PAR-25-442. Participating NIH organizations include the National Center for Advancing Translational Sciences (NCATS), National Eye Institute (NEI), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Dental and Craniofacial Research (NIDCR), and National Institute of Mental Health (NIMH). The overarching goal of this opportunity is to advance early-stage research focused on currently undruggable targets in the context of intractable human diseases by supporting innovative strategies and preclinical development of novel agents or methods selective for such targets. This grant supports projects exploring target classes considered undruggable through conventional therapies, such as intrinsically disordered proteins, RNAs, organelles, and metabolites, which are often implicated in diseases with limited or no effective treatment options. Applicants are expected to identify such a target class and propose a viable method or agent to modulate it, producing proof-of-concept data that could lay the foundation for broader applications. Projects that target well-trodden druggable classes or diseases with existing effective therapies are considered low priority. The R21 grant mechanism supports exploratory research and does not require preliminary data. However, projects must be rigorously designed and feasible within the two-year funding window. Applicants may request up to $275,000 in direct costs for the full project period, not exceeding $200,000 in any single year. The opportunity is open to a wide array of eligible entities, including higher education institutions, nonprofits, for-profit organizations, government entities, and tribal organizations, though foreign organizations are not eligible to apply. Applications must be submitted electronically via NIH ASSIST, Grants.gov Workspace, or institutional system-to-system solutions. The first open date for applications is September 17, 2025, with application due dates occurring on October 17, 2025; May 15, 2026; and February 17 of both 2027 and 2028. Letters of Intent are due 30 days prior to each application deadline. The program does not accept applications involving clinical trials or cancer-focused research. Comprehensive registration in SAM, Grants.gov, and eRA Commons is required for submission. Review criteria include the importance and innovation of the research, the rigor and feasibility of the approach, and the qualifications of the investigators and the research environment. Specific considerations will be given to how well the project addresses undruggable targets and intractable diseases, as well as the specificity and applicability of the proposed approach. For scientific inquiries, Dr. Karlie Sharma at NCATS can be contacted at karlie.sharma@mail.nih.gov or 301-451-4965.

Read and follow the R21 Application Guide. Ensure all registrations and data sharing plans are complete and compliant.