@article{discovery10075310,
            note = {Copyright {\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.},
         journal = {Journal of the American Chemical Society},
            year = {2019},
           title = {Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening},
            issn = {0002-7863},
          author = {Resnick, E and Bradley, A and Gan, J and Douangamath, A and Krojer, T and Sethi, R and Geurink, PP and Aimon, A and Amitai, G and Bellini, D and Bennett, J and Fairhead, M and Fedorov, O and Gabizon, R and Gan, J and Guo, J and Plotnikov, A and Reznik, N and Ruda, GF and D{\'i}az-S{\'a}ez, L and Straub, VM and Szommer, T and Velupillai, S and Zaidman, D and Zhang, Y and Coker, AR and Dowson, CG and Barr, HM and Wang, C and Huber, KVM and Brennan, PE and Ovaa, H and von Delft, F and London, N},
        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.},
             url = {https://doi.org/10.1021/jacs.9b02822}
}