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Functional genomics to uncover drug mechanism of action

Abstract

The upswing in US Food and Drug Administration and European Medicines Agency drug approvals in 2014 may have marked an end to the dry spell that has troubled the pharmaceutical industry over the past decade. Regardless, the attrition rate of drugs in late clinical phases remains high, and a lack of target validation has been highlighted as an explanation. This has led to a resurgence in appreciation of phenotypic drug screens, as these may be more likely to yield compounds with relevant modes of action. However, cell-based screening approaches do not directly reveal cellular targets, and hence target deconvolution and a detailed understanding of drug action are needed for efficient lead optimization and biomarker development. Here, recently developed functional genomics technologies that address this need are reviewed. The approaches pioneered in model organisms, particularly in yeast, and more recently adapted to mammalian systems are discussed. Finally, areas of particular interest and directions for future tool development are highlighted.

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Figure 1: Selected events and discoveries important for functional genomics for drug MoA.
Figure 2: Molecular barcode tags allow quantification of cells in a complex mixture under different conditions.
Figure 3: Gene-trap mutagenesis and quantification.

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Acknowledgements

I wish to thank H. Pickersgill of Life Science Editors for critical reading and editing of the manuscript.

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Correspondence to Sebastian M B Nijman.

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The author is cofounder and shareholder of Haplogen, GmbH. The company employs haploid genetics in the area of infectious disease.

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Nijman, S. Functional genomics to uncover drug mechanism of action. Nat Chem Biol 11, 942–948 (2015). https://doi.org/10.1038/nchembio.1963

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