期刊
CHEMBIOCHEM
卷 17, 期 15, 页码 1456-1463出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201600184
关键词
bromodomains; conformational plasticity; epigenetics; NMR; protein-protein interactions
资金
- Major National Scientific Research Projects [2012CB917201, 2014CB910604]
- National Natural Science Foundation of China [21273216]
The complex biology associated with inhibition of bromodomain and extra-terminal (BET) domains by chemical probes has attracted increasing attention, and there is a need to identify non-BET bromodomain (BD) inhibitors. Several potent inhibitors of the BRD9 BD have recently been discovered, with anticancer and anti-inflammation activity. However, its paralogue, BRD7 BD, remains unexploited. Here, we identified new chemotypes targeting BRD7 BD by using NMR fragment-based screening. BRD7/9 BDs exhibit similar patterns of chemical-shift perturbation upon the titration of hit compound 1. The crystal structure revealed that 1 repels the Y222 group of BRD9 BD in a similar way to that for butyryllysine, but not acetyllysine and known inhibitors. Hit 1 induced less rearrangement of residue F161 of BRD9 BD than acetyllysine, butyryllysine, and crotonyllysine. Our study provides structural insight into a new generation of butyryllysine mimics for probing the function of BRD7/9 BD.
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