Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening

Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening. Resnick, E., Bradley, A., Gan, J., Douangamath, A., Krojer, T., Sethi, R., Geurink, P., P., Aimon, A., Amitai, G., Bellini, D., Bennett, J., Fairhead, M., Fedorov, O., Gabizon, R., Gan, J., Guo, J., Plotnikov, A., Reznik, N., Ruda, G., F., Díaz-Sáez, L., Straub, V., M., Szommer, T., Velupillai, S., Zaidman, D., Zhang, Y., Coker, A., R., Dowson, C., G., Barr, H., M., Wang, C., Huber, K., V., Brennan, P., E., Ovaa, H., von Delft, F., & London, N. Journal of the American Chemical Society, 141(22):8951-8968, American Chemical Society, 6, 2019.

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Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening [link]

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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 highlight...

@article{
 title = {Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening},
 type = {article},
 year = {2019},
 pages = {8951-8968},
 volume = {141},
 websites = {http://pubs.acs.org/doi/10.1021/jacs.9b02822},
 month = {6},
 publisher = {American Chemical Society},
 day = {5},
 id = {fa35c245-3b40-354d-9fbe-7e3e0101aa16},
 created = {2019-06-06T08:26:02.146Z},
 accessed = {2019-06-06},
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 last_modified = {2019-08-07T17:40:12.643Z},
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 citation_key = {Resnick2019},
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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 highlight...},
 bibtype = {article},
 author = {Resnick, Efrat and Bradley, Anthony and Gan, Jinrui and Douangamath, Alice and Krojer, Tobias and Sethi, Ritika and Geurink, Paul P. and Aimon, Anthony and Amitai, Gabriel and Bellini, Dom and Bennett, James and Fairhead, Michael and Fedorov, Oleg and Gabizon, Ronen and Gan, Jin and Guo, Jingxu and Plotnikov, Alexander and Reznik, Nava and Ruda, Gian Filippo and Díaz-Sáez, Laura and Straub, Verena M. and Szommer, Tamas and Velupillai, Srikannathasan and Zaidman, Daniel and Zhang, Yanling and Coker, Alun R. and Dowson, Christopher G. and Barr, Haim M. and Wang, Chu and Huber, Kilian V.M. and Brennan, Paul E. and Ovaa, Huib and von Delft, Frank and London, Nir},
 doi = {10.1021/jacs.9b02822},
 journal = {Journal of the American Chemical Society},
 number = {22}
}

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