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Target engagement

Shining a light

Nature Chemical Biology volume 13, pages 133–134 (2017)Cite this article

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The ability to measure the binding of a compound to its intended target in live cells or tissue is a critical parameter for drug discovery. A new method using polarized light microscopy adds to the current toolbox by enabling monitoring of target engagement in vitro and in vivo at single-cell resolution.

There are various formats of target-engagement assays, which can be used to demonstrate that a compound binds to its designated target in cells. Some approaches utilize direct physical binding (for example, chemical proteomics) whereas others, such as fluorescence or bioluminescence resonance energy transfer (FRET and BRET, respectively)-based assays, rely on spatial proximity as a surrogate (for a recent review of general target engagement approaches see ref. 4). All of these strategies have individual benefits, as well as limitations such as requirements for chemical modification of the compound of interest, tagging of proteins, or both. Furthermore, the transfer of these assays into tissue or even animal models represents a substantial challenge. The cellular thermal shift assay (CETSA)5 provides a label-free method that addresses some of these potential issues. The power and potential scope of this approach has recently been demonstrated by the successful combination of CETSA and quantitative protein mass spectrometry6,7,8. However, more data are needed to better estimate the CETSA-compatible fraction of the proteome. Considering the heterogeneity and context dependence of cellular responses to various stimuli9, an ideal method would also enable the measurement of drug target engagement on the single-cell level.

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Figure 1: Measuring cellular target engagement of unlabeled drugs by using fluorescence polarization microscopy in combination with companion imaging probes (CIPs).

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  1. Nuffield Department of Medicine, Kilian V.M. Huber is at the Structural Genomics Consortium and the Target Discovery Institute, University of Oxford, Oxford, UK.,

    Kilian V M Huber

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Correspondence to Kilian V M Huber.

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Huber, K. Shining a light. Nat Chem Biol 13, 133–134 (2017). https://doi.org/10.1038/nchembio.2295

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