Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains
作者： Terry D. Crawford , Vickie Tsui , E. Megan Flynn , Shumei Wang , Alexander M. Taylor
DOI: 10.1021/ACS.JMEDCHEM.6B00264
关键词: TAF1 、 Highly selective 、 Structure–activity relationship 、 BRD4 、 Bromodomain 、 RNA-binding protein 、 Transcription (biology) 、 Förster resonance energy transfer 、 Biochemistry 、 Chemistry 、 Stereochemistry
摘要: The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent highly selective inhibitors effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing N-methyl group were designed directing toward conserved water pocket, two distinct binding conformations then observed. either directly displaced rearranged solvent network, as in BRD4(1) TAF1(2), or induced narrow channel adjacent lipophilic shelf, BRD9 CECR2. preference for provided selectivity handles useful future lead optimization efforts BRD9, CECR2, TAF1(2) inhibitors.
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