Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains

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.

非BET溴结构域（non-BET bromodomains）所发挥的生物学功能迄今仍未得到充分解析，因此亟需鉴定出强效且高选择性的抑制剂，以有效探究单个溴结构域蛋白的生物学特性。研究人员从6-甲基吡咯并吡啶酮（6-methyl pyrrolopyridone）片段中筛选得到一种配体高效的非选择性溴结构域抑制剂。通过设计小体积疏水取代基替换N-甲基基团，使其指向保守溴结构域水口袋，随后观察到两种截然不同的结合构象：一类取代基可直接置换并重排保守溶剂网络，如BRD4(1)与TAF1(2)中的结合模式；另一类则诱导形成一条毗邻亲脂性支架的狭窄疏水通道，例如BRD9与CECR2的结合状态。不同取代基对单个溴结构域的结合偏好性，可为未来针对选择性BRD9、CECR2及TAF1(2)抑制剂的先导化合物优化工作提供极具价值的选择性调控靶点。