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Rapid covalent-probe discovery by electrophile-fragment screening

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Resnick, Efrat, Bradley, Anthony, Gan, Jinrui, Douangamath, Alice, Krojer, Tobias, Sethi, Ritika, Geurink, Paul P., Aimon, Anthony, Amitai, Gabriel, Bellini, Dom et al.
(2019) Rapid covalent-probe discovery by electrophile-fragment screening. Journal of the American Chemical Society, 141 (22). pp. 8951-8968. doi:10.1021/jacs.9b02822

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Official URL: http://dx.doi.org/10.1021/jacs.9b02822

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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.

Item Type: Journal Article
Subjects: Q Science > QC Physics
Q Science > QP Physiology
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Electrophiles , Chemical inhibitors , Enzyme inhibitors
Journal or Publication Title: Journal of the American Chemical Society
Publisher: American Chemical Society
ISSN: 0002-7863
Official Date: 7 May 2019
Dates:
DateEvent
7 May 2019Published
Volume: 141
Number: 22
Page Range: pp. 8951-8968
DOI: 10.1021/jacs.9b02822
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
1097/16Israel Science Foundationhttp://dx.doi.org/10.13039/501100003977
UNSPECIFIEDRising Tide UK‏ http://viaf.org/viaf/260112048
UNSPECIFIEDIsrael Cancer Research Fundhttp://dx.doi.org/10.13039/100001698
3-14763Ministry of Science and Technology, Israelhttp://dx.doi.org/10.13039/501100006245
724.013.002[NWO] Nederlandse Organisatie voor Wetenschappelijk Onderzoekhttp://dx.doi.org/10.13039/501100003246
UNSPECIFIED[SGC] Structural Genomics Consortiumhttp://viaf.org/viaf/128064913
UNSPECIFIEDWeizmann Institute of Sciencehttp://dx.doi.org/10.13039/501100001735

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