Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains
Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains
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DOI：
10.1021/acs.jmedchem.6b00264
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发表时间：
2016-06-09
影响因子：
7.3
通讯作者：
Cochran, Andrea G.
中科院分区：
文献类型：
--
作者：
Crawford, Terry D.;Tsui, Vickie;Cochran, Andrea G.
非BET溴结构域所起的生物学作用仍然知之甚少，因此。因此，必须鉴定有效的和高选择性的抑制剂，以有效地探索单个溴结构域蛋白的生物学。从6-甲基吡咯并吡啶酮片段中鉴定出配体有效的非选择性溴结构域抑制剂。小的疏水取代基取代N-甲基基团被设计为指向保守的溴结构域水口袋，然后观察到两种不同的结合构象。取代基直接置换和重排保守的溶剂网络，如在BRD 4（1）和TAF 1（2）中，或诱导邻近亲脂性架的窄疏水通道，如在BRD 9和CECR 2中。对单个溴结构域的不同取代基的偏好提供了可用于选择性BRD 9、CECR 2和TAF 1（2）抑制剂的未来先导物优化工作的选择性处理。
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore. imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.