The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis

Abstract

SignificanceThe ReFRAME collection of 12,000 compounds is a best-in-class drug repurposing library containing nearly all small molecules that have reached clinical development or undergone significant preclinical profiling. The purpose of such a screening collection is to enable rapid testing of compounds with demonstrated safety profiles in new indications, such as neglected or rare diseases, where there is less commercial motivation for expensive research and development. Providing the academic and nonprofit research community access to a high-value compound collection and related screening data in an open-access platform should provide new tool compounds for biomedical research, as well as accelerate drug-discovery and/or development programs aimed at developing new therapies for diverse unmet medical needs.

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

“…The LOPAC®1280 library is a collection of 1,280 pharmacologically active compounds, covering all the major target classes, including kinases, GPCRs, neurotransmission and gene regulation (Sigma). The ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library, built at the California Institute for Biomedical Research (Calibr) 27 , contains approximately 12,000 high-value molecules assembled by combining three databases (Clarivate Integrity, GVK Excelra GoStar and Citeline Pharmaprojects) for fast-track drug discovery. This library contains US Food and Drug Administration (FDA)-approved/registered drugs (~35 %), investigational new drugs (~58 %), and preclinical compounds (~3 %).…”

“…Since the results of the LOPAC®1280 HTS analysis indicated that these assay conditions were suitable to progress to a large-scale screen, we used this experimental design to screen the comprehensive ReFRAME drug repurposing collection. This library is an inclusive collection of nearly 12,000 chemical compounds, that have been either FDA-approved or registered outside the US, entered clinical trials, or undergone significant pre-clinical characterization 27 . Specifically, 11,987 compounds were arrayed in 384-well plates at a final concentration of 5 µM.…”

“…While these targeted repurposing strategies provide potentially rapid trajectories toward an approved treatment, an unbiased large-scale evaluation of known drugs and clinical candidates can identify additional unanticipated therapeutic options with accelerated evaluation for the treatment of COVID-19 disease. Here, we describe a high-throughput repositioning screen using the commercial library of 1,280 pharmacologically active compounds LOPAC®1280 and the ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) drug collection, a comprehensive openaccess library of ~12,000 clinical-staged or approved small molecules respectively, to identify existing drugs that harbor antiviral activity against SARS-CoV-2 in a cell-based assay 27,28 . The ReFRAME library has previously been used to successfully identify the anti-inflammatory auranofin as a potential therapy for tuberculosis 29 , the approved drug clofazimine as a potent antiparasitic compound that is now being tested for efficacy against Cryptosporidium 30 , and has also been used to identify and optimize the FDAapproved antifungal drug itraconazole as a novel efficacious molecule suitable for chronic administration as an anti-fibrotic 31 .…”

High-throughput screening of the ReFRAME library identifies potential drug repurposing candidates forTrypanosoma cruzi

“…This has the potential to speed up drug development efforts, reduce costs and lower the chance of adverse events presenting in clinical trials. The ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library, a comprehensive set of molecules with tested clinical safety, has been previously used to identify potential drug repurposing hits for neglected tropical diseases (7,8). In this work, we screened 7,680 compounds from this library against the medically relevant intracellular, amastigote form of T. cruzi infecting mouse myoblasts using a high-throughput, phenotypic cellular imaging assay that our group has successfully used in previous studies to identify novel antitrypanosomal agents (9)(10)(11).…”

A phenotypic screening platform utilising human spermatozoa identifies new compounds with contraceptive activity

“…The bespoke computational pipeline quantitatively evaluates compound activity against both attributes thus achieving unprecedented throughput. The platform was used to identifying inhibitors from a unique 12,000 molecule ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library, which represents the most comprehensive collection of drugs available, as it contains nearly all the small molecules that have achieved regulatory approval and others that have undergone varying degrees of clinical development or have had significant preclinical profiling (Janes et al , 2018). This advance opens up the possibility of accelerated male contraceptive development by allowing drug repurposing, target identification as well as screening of chemical diversity libraries for novel medicinal chemistry start points.…”