Repurposing for neglected diseases

Data collection of existing small-molecule drugs could expedite potential therapies

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LA JOLLA, Calif.—Scientists at Calibr, a non-profit drug discovery division of Scripps Research, are using an extensive library of more than 12,000 small-molecule drugs deemed appropriate for direct use in humans to help researchers to repurpose drugs for treating a variety of illnesses. The ReFRAME (Repurposing, Focused Rescue and Accelerated Medchem) drug repurposing collection, which was compiled using widely used commercial drug databases (Clarivate Integrity, GVK Excelra GoStar and Citeline Pharmaprojects), offers hope for treating diseases that kill millions worldwide.
Calibr researchers also mined patent filings to find drug candidates that are not yet available on these databases but appear to be potential therapies for diseases other than their original indications. Calibr then launched a campaign to garner physical samples of the compounds. They bought approximately 7,000 compounds and synthesized roughly 5,000 others. The project, which included 500 chemists over an 18-month period, is still ongoing. It has enabled Calibr to identify a host of unique compounds that have never been collected in one place and make them more readily available to researchers.
“The idea came from an overarching concept that existing drugs could be put together to maximize the potential of drugs that had already been tested, saving time and cost,” explained Dr. Arnab Chatterjee, vice president of medicinal chemistry at Calibr and lead researcher on the project. “The idea of ReFRAME is to democratize compound screening for biologists. It is available at no cost to them. The only requirement is that they make data publicly available. We provide guidance on data analysis.”
Dr. Pete Schultz, president and CEO of Scripps Research and Calibr and a lead researcher on the ReFRAME project, added, “ReFRAME takes the concept of accelerating impact on patients through repurposing existing drugs to a new level, offering great potential for finding much-needed therapies more quickly and cost-effectively. The drugs we’ve assembled in ReFRAME have already been shown safe in humans, making them an incredibly valuable resource for tackling areas of urgent unmet medical need, especially neglected tropical diseases.”
Thanks to the ReFRAME initiative, two FDA-approved drugs—one to treat tuberculosis and another to treat the parasite Cryptosporidium spp., a key cause of severe diarrhea—have moved from concept to clinical trials in a few years, instead of much longer timelines that often characterize new drug development. The initial drugs identified for possible repurposing using ReFRAME were the leprosy drug clofazimine and the arthritis drug auranofin. Calibr is working with the University of Washington, which is sponsoring a Phase 2A clinical trial in Malawi, and the Bill and Melinda Gates Foundation to study the safety, tolerability, pharmacokinetics and efficacy of clofazimine for treating cryptosporidiosis in HIV-positive patients. The other drug, Auranofin, is being tested for treating tuberculosis in a clinical trial taking place in South Africa.
Calibr researchers also used ReFRAME to identify two other compounds that seemed effective against Cryptosporidium spp., as reported in the Proceedings of the National Academy of Sciences. Using the institute’s high-throughput screening facility, the researchers tested all 12,000 compounds against Cryptosporidium. Only one drug, nitazoxanide, which is not highly potent and not effective in patients with compromised immune systems, is approved for treating Cryptosporidium infection. There is little other drug discovery research on it due to a lack of commercial interest, but repurposing can change that.
Calibr researchers hope to be involved in facilitating repurposed therapies for other infectious diseases in the developing world. They have created an open-access data portal ( to share the results of their ReFRAME screening experiments with other researchers, to encourage additional follow-up and maximize the impact of the screening collection.
Chatterjee concluded, “Our emphasis is to enable scientists working on neglected diseases to have access to molecules. They are sent to all parts of the world and provide great value to places with no commercial interest as well as places where there is. The key goal is to put drug data resources, mechanisms of action and indications in a public portal where they are available to researchers free of charge, as well as to provide the actual molecules. While they are of great value to everyone, they are especially useful to people who would not otherwise have access to them.”

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