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  • Review Article
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Applications of chemogenomic library screening in drug discovery

Nature Reviews Drug Discovery volume 16, pages 285–296 (2017)Cite this article

Subjects

Key Points

  • A chemogenomic library is a collection of well-defined pharmacological agents. A hit from such a set in a phenotypic screen suggests that the annotated target or targets of the probe molecules are involved in the phenotypic perturbation.

  • The creation and utility of a number of chemogenomic libraries have been described, by academia and industry, and some are commercially available.

  • Chemogenomic screening has the potential to expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications include drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.

  • Target identification from phenotypic screening can benefit from the integration of small-molecule chemogenomics with genetic approaches, such as RNA-mediated interference and CRISPR–Cas9.

  • Current limitations of chemogenomic screening include small-molecule polypharmacology, misannotation of biological activity and false-positive results (deriving from compound fluorescence or luciferase reporter binding) for example, although opportunities to overcome these issues, particularly through the incorporation of computational techniques, are emerging.

  • 'Open innovation' and collaborative ventures across academia and industry are required to create and assemble the best pharmacological probes for chemogenomic libraries.

Abstract

The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications are explored, including drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.

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Figure 1: A typical chemogenomic screen sequence.
Figure 2: Gene families and biological pathways covered in example chemogenomic libraries.

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Acknowledgements

The authors thank the following for providing information regarding the chemogenomic libraries described in this Review: Michael Earley (Sigma-Aldrich; Library of Pharmacologically Active Compounds (LOPAC1280)); William Zuercher (University of North Carolina at Chapel Hill; Published Kinase Inhibitor Set); Craig Thomas (National Center for Advancing Translational Sciences; Mechanism Interrogation PlatE). They also thank the following Pfizer employees for their contributions to the creation of the Pfizer chemogenomic library: Samit Bhattacharya, Markus Boehm, Philip Carpino, Agustin Casimiro-Garcia, Thomas Chappie, Ye Che, Eugene Chekler, Leslie Dakin, Robert Dow, David Edmonds, Andrew Fensome, Kevin Filipski, Adam Gilbert, Rose Gonzales, Ariamala Gopalsamy, David Gray, Matthew Hayward, Jaclyn Henderson, David Hepworth, Peter Jones, Neelu Kaila, John Kath, Jacquelyn Klug-McLeod, Esther Lee, Bruce Lefker, Allyn Londregan, Frank Lovering, Eric Marr, Christopher McClendon, Dale McLeod, Arjun Narayanan, Whitney Nolte, Dafydd Owen, Robert Owen, David Piotrowski, David Pryde, Brian Raymer, Yong Ren, Lee Roberts, Matthew Sammons, Mark Schnute, Sarah Skerratt, Ian Storer, Joseph Strohbach, Nigel Swain, Atli Thorarensen, Ray Unwalla, Michael Vazquez, Fabien Vincent, Christoph Zapf and Lei Zhang.

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  1. Mark E. Bunnage

    Present address: Present address: Vertex Pharmaceuticals, 50 Northern Avenue, Boston, Massachusetts 02210, USA.,

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  1. Medicine Design, Pfizer, 610 Main Street, Cambridge, 02139, Massachusetts, USA

    Lyn H. Jones & Mark E. Bunnage

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L.H.J. and M.E.B. were Pfizer employees and shareholders during the preparation of this Review.

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PowerPoint slides

Glossary

Chemogenomic screening set

Collections of small-molecule pharmacological modulators that have well-annotated biological activity.

Causal Reasoning Engine

An algorithm that uses omic data and causal statements from the literature to infer upstream molecular events and derive mechanistic hypotheses linked to the observed change.

Multiparameter optimizations

Algorithms that allow several variables to be balanced and assessed on the basis of their importance relative to the specified objective.

Pan-assay interference compounds

(PAINs). Compounds that often appear as false-positive hits in screens owing to promiscuous binding, fluorescence, redox activity or metal chelation effects.

High-content

A term used in this Review to describe a cell-based assay that measures several parameters, often using automated imaging analysis.

Perturbagens

Modalities — such as genetic reagents (for example, short interfering RNA and short hairpin RNA), small molecules, proteins or peptides — that alter the phenotype of a cell in some way.

Pharmacogenomic

A term that refers to the study of how genetics can alter responses to drugs.

Target occupancy

The interaction between a chemical probe or drug and its target, resulting in a biological response.

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Jones, L., Bunnage, M. Applications of chemogenomic library screening in drug discovery. Nat Rev Drug Discov 16, 285–296 (2017). https://doi.org/10.1038/nrd.2016.244

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