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Drug repurposing—also termed drug repositioning—is the systematic investigation of existing, approved, or clinical-stage therapeutics to identify new pharmacological indications outside their original clinical scope. By leveraging existing preclinical toxicology, pharmacokinetic profiles, and manufacturing data, research teams accelerate translational timelines toward clinical validation and regulatory submission.
Short answer
Drug repurposing identifies novel therapeutic applications for established approved, clinical-phase, or shelved compounds. By deploying phenotypic screening, chemoproteomics, and curated phenotypic libraries, translational investigators bypass early de novo discovery cycles, utilizing established pharmacology and existing safety profiles to accelerate candidates toward Investigational New Drug (IND) filings and regulatory approval under abbreviated pathways such as FDA Section 505(b)(2).
Definition and scope
Drug repurposing forms a core pillar of modern pharmacology and translational drug development. In experimental workflows, repurposing differs fundamentally from de novo chemical discovery: rather than synthesizing and screening uncharacterized chemical entities from scratch, investigators evaluate compounds that possess established chemical structures, defined physical properties, and characterized biological activities. Understanding what is pharmacology provides the conceptual foundation for evaluating how these known chemical structures modulate distinct molecular targets across different organ systems.
The scope of drug repurposing spans three operational domains:
- On-target repurposing: Applying a drug against its known biological target to treat a distinct disease condition that shares identical pathological mechanisms.
- Off-target repositioning: Identifying previously unrecognized binding interactions between a known chemical scaffold and unexpected secondary protein targets, often discovered through high-throughput phenotypic assays or target deconvolution.
- Formulation and delivery modification: Developing novel delivery matrices, target tissues, or combination regimens that alter bio-distribution or overcome historical bioavailability limitations.
How it works or how it is used in practice
Translational research teams execute drug repurposing workflows through integrated experimental pipelines that link chemical repositories, phenotypic screening, and regulatory de-risking infrastructure.
Curated compound screening libraries
Screening initiatives rely on curated physical repositories of annotated compounds. The Broad Institute Drug Repurposing Hub serves as a central reference platform, cataloging 6,801 compounds available in single- and multi-dose formats. This curated collection includes annotations across 6,125 distinct tool and therapeutic compounds, comprising 2,369 FDA-approved pharmaceuticals, 1,619 compounds evaluated in clinical phases 1 through 3, 96 withdrawn agents, and 2,041 preclinical tool compounds. Data outputs from these high-throughput profiling screens are distributed in Gene Cluster Text (GCT) format, enabling researchers to compute connectivity scores and visualize high-dimensional response signatures via t-distributed stochastic neighbor embedding (t-SNE).
Public repositories and bioactivity databases
Investigative workflows integrate molecular structure data from chemical repositories such as the PubChem chemistry bioassay data repository, cross-referencing published bioactivity datasets with disease-specific phenotypic screens. Structural activity relationships and target binding profiles documented in the Journal of Medicinal Chemistry provide chemical optimization baselines when analog synthesis is needed to improve target selectivity.
Preclinical development and translational funding infrastructure
To overcome funding hurdles in late preclinical development—often termed the translational “valley of death”—federal programs provide direct resource allocation for repurposing candidates. The National Center for Advancing Translational Sciences (NCATS) maintains dedicated translational support mechanisms:
- Therapeutics for Rare and Neglected Diseases (TRND): NCATS TRND partners with academic and non-profit investigators to conduct late-stage preclinical work. TRND provides direct operational access to NIH laboratories, contract research capabilities, and regulatory expertise to support rare disease projects through IND filing.
- Bridging Interventional Development Gaps (BrIDGs): BrIDGs provides resource access to synthesis, GMP formulation, and regulatory toxicology required to advance therapeutic candidates into human clinical trials.
Types and related concepts
Drug repurposing methodologies employ diverse computational, phenotypic, and target-based frameworks. The table below delineates the primary approaches used in laboratory workflows.
| Approach | Primary methodology | Key data asset or repository | Primary translational hurdle |
|---|---|---|---|
| Phenotypic screening | High-throughput cell viability and reporter assays across curated libraries | Broad Institute Repurposing Hub (6,801 compounds) | Target deconvolution and mechanism clarification |
| Target-based screening | Biochemical binding assays, surface plasmon resonance (SPR), cryo-EM | PubChem BioAssay, Protein Data Bank (PDB) | Translating binding affinity to cellular efficacy |
| Bioinformatic transcriptomics | Connectivity mapping matching disease gene expression to drug reversal profiles | Connectivity Map (CMap), GCT expression matrices | Discrepancies between cell line transcriptomes and in vivo tissue |
| Clinical real-world evidence | Retrospective analysis of electronic health records and adverse event data | FDA Adverse Event Reporting System (FAERS) | Confounding variables and non-randomized patient exposure |
Where it matters for labs, clinics, or supply decisions
Drug repurposing directly impacts resource allocation, laboratory compliance, and clinical development strategy in research environments.
Regulatory filings and 505(b)(2) pathways
In the United States, drug repurposing programs utilize abbreviated regulatory mechanisms codified in 21 U.S.C. § 355(b)(2) (Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act). Unlike standard 505(b)(1) New Drug Applications (NDAs) that require complete de novo nonclinical and clinical testing, a 505(b)(2) submission allows sponsors to rely in part on published scientific literature or FDA’s prior safety findings for the reference listed drug. This pathway reduces animal testing requirements while requiring bridge studies for new indications, routes of administration, or dosing ranges.
Preclinical safety and laboratory compliance
Even when a chemical agent has an established human safety history, repurposing for a new indication or novel delivery route mandates rigorous IND-enabling studies. Pivotal safety pharmacology, genotoxicity, and repeat-dose toxicology studies supporting IND filings must adhere strictly to Good Laboratory Practice standards outlined under 21 CFR Part 58 GLP requirements. Understanding the formal regulatory boundary between research pharmacology and clinical practice is discussed in the analysis of pharmacy vs pharmacology.
Common misunderstandings
- Myth: Repurposed drugs bypass preclinical safety testing. While historical safety data reduces initial risk, changing a drug’s target patient demographic, dosage, or administration route often requires new toxicity, bioavailability, and pharmacokinetic bridge studies under GLP guidelines.
- Myth: Repurposed drugs cannot obtain patent protection. While composition-of-matter patents for the active pharmaceutical ingredient may have expired, researchers and institutions can secure intellectual property via method-of-use claims, novel formulation patents, dosing regimens, and orphan drug designations.
- Myth: Any active library hit translates directly to clinical dosing. In vitro phenotypic activity frequently occurs at micromolar concentrations that cannot be achieved safely in vivo without severe toxicity, requiring careful pharmacokinetic evaluation.
Frequently asked questions
What is the difference between drug repurposing and drug repositioning?
In research practice, the terms are often used interchangeably. However, “drug repurposing” typically refers to identifying new disease indications for approved or established drugs, whereas “drug repositioning” frequently describes finding alternative indications for clinical-stage candidates that failed efficacy endpoints in their initial target indication.
What is the Broad Institute Drug Repurposing Hub?
The Drug Repurposing Hub is a curated collection of 6,801 compounds maintained by the Broad Institute of MIT and Harvard. It provides annotated pharmaceutical compounds, clinical trial status metadata, mechanism-of-action data, and Gene Cluster Text (GCT) datasets for high-throughput screening.
How does FDA 505(b)(2) support drug repurposing?
Under 21 U.S.C. § 355(b)(2), sponsors can submit an NDA that relies partially on published scientific literature or the FDA’s prior findings of safety and efficacy for an approved drug, substantially reducing redundant preclinical development timelines.
Sources
- Broad Institute. “Repurposing Data Portal.” Accessed 2026-11-07. https://clue.io/repurposing
- Corsello, S. M., Bittker, J. A., Liu, Z., et al. “The Drug Repurposing Hub: a next-generation drug library and information resource.” Nature Medicine 23, 405–408 (2017). DOI: 10.1038/nm.4306.
- National Center for Advancing Translational Sciences (NCATS). “Therapeutics for Rare and Neglected Diseases (TRND).” National Institutes of Health. Accessed 2026-11-07. https://ncats.nih.gov/trnd
- National Center for Advancing Translational Sciences (NCATS). “Bridging Interventional Development Gaps (BrIDGs).” National Institutes of Health. Accessed 2026-11-07. https://ncats.nih.gov/bridgs
- Legal Information Institute, Cornell Law School. “21 U.S. Code § 355 – New drugs.” Accessed 2026-11-07. https://www.law.cornell.edu/uscode/text/21/355
