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

The “Expanding the Target Landscape by Drugging the Undruggable (R21 Clinical Trial Not Allowed)” funding opportunity is administered by the National Institutes of Health (NIH), through a consortium of participating organizations, including the National Center for Advancing Translational Sciences (NCATS), the National Eye Institute (NEI), the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute of Mental Health (NIMH), and, as of July 29, 2025, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). This initiative supports exploratory and early-stage research aimed at addressing the challenges posed by “undruggable” targets in intractable human diseases—targets that conventional therapeutic approaches cannot effectively engage. NCATS' mission underpins the rationale for this funding opportunity. The Center is focused on transforming the translational science process to accelerate the development of diagnostics and treatments. It pursues innovative methodologies to address shared biological mechanisms across diseases, improve patient-representative models for testing, and optimize clinical trial frameworks. This funding opportunity aligns with these goals by soliciting projects that investigate and develop approaches to modulate undruggable biological targets such as intrinsically disordered proteins, RNAs, metabolites, and others. These targets have historically remained outside the reach of small molecule or biologic-based drug development strategies. Eligible applicants are encouraged to propose projects that fill existing gaps in the treatment of intractable diseases. Proposals must clearly identify a relevant undruggable target class, justify its relevance to human disease, and propose a method, agent, or technology that can be used as a use case to demonstrate proof of concept. Projects that also provide a pathway for broader applicability across the entire undruggable target class are encouraged. Studies focusing on already druggable targets or diseases with many existing treatments are considered low priority. Cancer-focused projects are explicitly excluded from eligibility. The funding mechanism is an R21 Exploratory/Developmental Research Grant. The total budget allowed over a two-year project period is $275,000 in direct costs, with no more than $200,000 allowed in any single year. No clinical trials are permitted under this opportunity. NIH will determine the number of awards based on appropriations and merit. Applicants must comply with the application instructions in the Research (R) section of the NIH “How to Apply” guide and submit through one of the accepted systems such as ASSIST, Grants.gov Workspace, or their institutional system. Key deadlines include an opening date for application submission on September 17, 2025, with application deadlines recurring on October 17, 2025; May 15, 2026; February 17, 2027; and February 17, 2028. Letters of Intent are due 30 days prior to the respective application deadlines. The earliest project start date is typically four to five months after each submission deadline, depending on the peer review and advisory council schedule. Applications must be submitted by 5:00 PM local time of the applicant organization, and late applications will not be accepted unless due to justifiable system issues. Eligibility spans a wide range of organizations including higher education institutions, nonprofits, for-profit entities including small businesses, and various governmental entities. Foreign organizations are not eligible. Applicants must complete all required registrations (e.g., SAM, Grants.gov, eRA Commons) prior to submission. Contact persons for scientific and grant-related inquiries are listed by participating NIH institute, with key contacts including Dr. Karlie Sharma (NCATS), Dr. Yael Mandelblat-Cerf (NIMH), and Dr. James Boyce (NIAID), among others. Financial contacts are also provided. Applications will be reviewed for scientific and technical merit using NIH’s peer review system. Review criteria focus on the importance of the research, rigor and feasibility of the proposed approach, and the expertise of the investigators. Proposals that offer innovative solutions to longstanding treatment challenges will receive higher priority. Funding decisions will be based on scientific merit, availability of funds, and program relevance.

Projects focused on already druggable targets or cancer are deprioritized. Submit early to allow time for error correction.