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Methods Enzymol. 2018;610:27-58. doi: 10.1016/bs.mie.2018.09.013. Epub 2018 Oct 24.

Target Identification Using Chemical Probes.

Author information

1
Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, United Kingdom; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom.
2
Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom.
3
Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom; Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
4
Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom; Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom. Electronic address: gillian.farnie@sgc.ox.ac.uk.
5
Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom; Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom. Electronic address: fiona.mccann@kennedy.ox.ac.uk.
6
Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, Alzheimer's Research UK Oxford Drug Discovery Institute, University of Oxford, Oxford, United Kingdom. Electronic address: paul.brennan@sgc.ox.ac.uk.

Abstract

Chemical probes are small molecules with potency and selectivity for a single or small number of protein targets. A good chemical probe engages its target intracellularly and is accompanied by a chemically similar, but inactive molecule to be used as a negative control in cellular phenotypic screening. The utility of these chemical probes is ultimately governed by how well they are developed and characterized. Chemical probes either as single entities, or in chemical probes sets are being increasingly used to interrogate the biological relevance of a target in a disease model. This chapter lays out the core properties of chemical probes, summarizes the seminal and emerging techniques used to demonstrate robust intracellular target engagement. Translation of target engagement assays to disease-relevant phenotypic assays using primary patient-derived cells and tissues is also reviewed. Two examples of epigenetic chemical probe discovery and utility are presented whereby target engagement pointed to novel disease associations elucidated from poorly understood protein targets. Finally, a number of examples are discussed whereby chemical probe sets, or "chemogenomic libraries" are used to illuminate new target-disease links which may represent future directions for chemical probe utility.

KEYWORDS:

Cellular assays; Chemical probes; Epigenetics; Patient-derived cellular assays; Target engagement assays; Target identification

PMID:
30390803
DOI:
10.1016/bs.mie.2018.09.013
[Indexed for MEDLINE]

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