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Finding New Tricks For Old Drugs: An Efficient Route For Public-Sector Drug Discovery

Key Points

  • A case-study approach is used to show that screening approved, and frequently off-patent, drugs efficiently yields candidate medications suitable for clinical trials.

  • The first two cases highlight cell-based screens that identified medications potentially useful for amyotrophic lateral sclerosis and progressive multifocal leukoencephalopathy, and clinical trials are being planned to test both types of medications.

  • Screening off-patent and off-market medications also led to the discovery of the molecular target responsible for the serious side-effects of the 'Fen/Phen' appetite suppressant combination and to a rational approach to anorectic drug discovery and development.

  • Using a similar approach, candidate medications have also been identified for multiple myeloma (fluphenazine), Alzheimer's disease (non-steroidal anti-inflammatory drugs and glitazones) and various psychiatric disorders

  • Screening all clinically approved medications against both the 'druggable genome' and an array of cell-based readouts is predicted to yield a large number of new therapeutics.

Abstract

With the annotation of the human genome approaching completion, public-sector researchers — spurred in part by various National Institutes of Health Roadmap Initiatives — have become increasingly engaged in drug discovery and development efforts. Although large and diverse chemical libraries of 'drug-like' compounds can be readily screened to yield chemically novel scaffolds, transforming these 'chemical probes' into drugs is a daunting endeavour. A more efficient approach involves screening libraries of approved and off-patent medications; both phenotypic- and molecular target-based screening of 'old drugs' can readily yield compounds that could be immediately used in clinical trials. Using case studies, we describe how this approach has rapidly identified candidate medications suitable for clinical trials in disorders such as progressive multifocal leukoencephalopathy and amyotrophic lateral sclerosis. This approach has also led to the discovery of the molecular targets responsible for serious drug side effects, thereby allowing efficient 'counter-screening' to avoid these side effects.

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Figure 1: The road to drug discovery: phenotypic versus single-target approaches.
Figure 2: Identification of the 5-hydroxytryptamine 2A receptor as the JC virus co-receptor via a combination of phenotypic and receptorome-based screening reveals a novel strategy for treating progressive multifocal leukoencephalopathy.
Figure 3: Identification of a potentially prophylactic treatment for progressive multifocal leukoencephalopathy.
Figure 4: How to make a safe and effective anorectic agent.

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Acknowledgements

The authors thank D. Sheffler for figures related to the JC virus life cycle, W. Kroeze for editorial assistance and grants from the National Institutes of Health and the National Institute of Mental Health-Psychoactive Drug Screening Program for supporting the work in the authors' lab.

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Correspondence to Bryan L. Roth.

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B.L.R. is a co-inventor listed on patents related to serotonin-selective ligands for use in neuropsychiatric and other disorders.

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FURTHER INFORMATION

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Glossary

PHENOTYPIC SCREENS

A type of chemical screen in which cell responses, such as motility or membrane ruffling, are monitored as an index of drug action. Frequently, phenotypic screens are carried out using high-throughput microscopy and automated image capture and analysis.

MOLECULAR TARGET-BASED SCREENS

A type of chemical screen in which a single molecular target, such as a receptor or enzyme, is screened using a simplified readout such as fluorescence.

RECEPTOROMICS AND RECEPTOROME

Receptorome refers, ultimately, to the entire complement of 'receptors in the genome', although it is more commonly applied to that portion of the genome encoding G-protein-coupled receptors. Receptoromics represents tools and methods of analysis to study the receptorome.

KINOMICS AND KINOME

The kinome refers to the entire complement of protein kinases in a particular genome. Kinomics represents tools and methods of analysis to study the kinome.

COUNTER-SCREENING

The approach of screening candidate medications against an array of molecular targets to identify 'off-target' actions.

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O'Connor, K., Roth, B. Finding New Tricks For Old Drugs: An Efficient Route For Public-Sector Drug Discovery. Nat Rev Drug Discov 4, 1005–1014 (2005). https://doi.org/10.1038/nrd1900

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