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Mitigating risk in academic preclinical drug discovery

Nature Reviews Drug Discovery volume 14, pages 279–294 (2015)Cite this article

Subjects

Key Points

  • Academic drug discovery offers an opportunity to effectively harness curiosity-driven research to improve human and animal health, but it is not without risk.

  • We believe that the associated risks can be managed by considering at least five factors that affect the success or failure of projects: organization, target selection, assay design, medicinal chemistry and preclinical pharmacology.

  • This manuscript presents guidelines for reducing the risk that can be caused by poor planning in any of these areas.

Abstract

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology.

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Figure 1: Staying on the right track in academic drug discovery.
Figure 2: Linking academic researchers with translational resources.
Figure 3: Assembling the experts.
Figure 4: p-hydroxyarylsulfonamides as examples of nuisance compounds.
Figure 5: Interconnected stages and cycles in lead discovery project development.
Figure 6: Examples of less obvious problematic compounds.
Figure 7: Examples of suspicious and useful structure–activity relationships.

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Acknowledgements

J.L.D. was supported by the following funding bodies: an NIH predoctoral fellowship (F30 DK092026-01); a Pharmaceutical Research and Manufacturers of America Foundation predoctoral pharmacology/toxicology fellowship; and the Mayo Foundation. J.I. is supported by the intramural programme in the National Center for Advancing Translational Sciences (NCATS), at the NIH. M.A.W. acknowledges research funding from the NIH and the Minnesota Partnership for Biotechnology and Medical Genomics. The authors specifically acknowledge the helpful comments and corrections suggested by the referees. The authors also acknowledge K. Nelson for critical reading of the manuscript and the many other important contributions in the drug discovery community that, regrettably, could not be cited owing to space constraints.

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    Jayme L. Dahlin

  2. National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, 20850, Maryland, USA

    James Inglese

  3. National Human Genome Research Institute, Bethesda, 20892, Maryland, USA

    James Inglese

  4. Institute for Therapeutics Discovery and Development, University of Minnesota Twin Cities, 717 Delaware St SE, Room 609, Minneapolis, 55414, Minnesota, USA

    Michael A. Walters

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Selected examples of entities that promote translational research (PDF 113 kb)

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Common artefactual compound-mediated biological activities (PDF 118 kb)

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Examples of high-throughput screening assays (PDF 106 kb)

Glossary

Chemical probe

A well-characterized compound showing context-related selectivity that potently modulates a biochemical target or pathway in cells or in vivo.

Prodrugs

Compounds that are the metabolic precursors of drugs. Prodrugs can aid in drug delivery and can be new chemical entities.

Biomarkers

Factors that are objectively measured and evaluated as indicators of biological or pathological processes, or of pharmacological responses to therapeutic intervention.

Reporter gene assay

An assay in which an easily detectable reporter gene such as luciferase is fused to the promoter sequence of downstream target genes of the signalling pathway under investigation. Modulation of the pathway, such as activation or inhibition, will lead to changes in reporter gene expression (in the case of luciferase, these changes will be measured as luminescence).

Orthogonal assays

Corresponding assays used following, or in parallel to, the primary high-throughput screening assay to confirm compound activity that is independent of the primary assay technique.

Chemotypes

Chemical structure motifs or primary substructures that are common to a group of compounds.

Diversity-oriented synthesis

Efficient synthesis of a collection (library) of structurally diverse and complex small molecules that differ in stereochemistry, functional groups and molecular framework.

Pan-assay interference compounds

(PAINS). Compounds containing substructures that give rise to activity in assays irrespective of the biological target.

Off-target activities

Activities of a compound that differ from its designed or annotated mechanism of action. Off-target activities are often undefined.

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Dahlin, J., Inglese, J. & Walters, M. Mitigating risk in academic preclinical drug discovery. Nat Rev Drug Discov 14, 279–294 (2015). https://doi.org/10.1038/nrd4578

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