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Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening

Resnick, E; Bradley, A; Gan, J; Douangamath, A; Krojer, T; Sethi, R; Geurink, PP; ... London, N; + view all (2019) Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening. Journal of the American Chemical Society 10.1021/jacs.9b02822. (In press). Green open access

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Abstract

Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered nonselective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against 10 cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. In contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile-fragment screening as a practical and efficient tool for covalent-ligand discovery.

Type: Article
Title: Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/jacs.9b02822
Publisher version: https://doi.org/10.1021/jacs.9b02822
Language: English
Additional information: Copyright © 2019 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/10075310
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