The bromodomain and extra-terminal domain (BET) family of proteins are readers which specifically recognize histone-acetylated lysine residues. Each BET bromodomain protein contains two highly homologous domains: the first bromodomain (BD1) and the second bromodomain (BD2). Pan-BET bromodomain inhibition is a potential therapy for various cancers and immune-inflammatory diseases, but only few reported inhibitors show selectivity within the BET family. Herein, we identified a series of benzo[cd]indol-2(1H)-ones and pyrrolo[4,3,2-de]quinolin-2(1H)-ones with good selectivity for BET BD1. Through structure-based optimization, highly active and selective compounds are ultimately obtained. The representative compounds are the first reported inhibitors with selectivity more than 100-fold for BRD4(1) over BRD4(2). Among them, we further show that 68 (LT052) mediates BRD4/NF-κB/NLRP3 signaling inflammatory pathways with comparable protein expression and significantly improves symptoms of gout arthritis in a rat model. Therefore, selective pharmacological modulation of individual bromodomains could represent a strategy for the treatment of acute gouty arthritis.

中文翻译：

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发现苯并[cd] indol-2（1H）-和吡咯并[4,3,2-de]喹啉-2（1H）-作为溴结构域和末端结构域（BET）抑制剂，对第一个溴结构域具有选择性具有对急性痛风性关节炎的潜在高效率。

蛋白质的溴结构域和末端外结构域（BET）家族是特异识别组蛋白乙酰化赖氨酸残基的阅读器。每个BET溴结构域蛋白都包含两个高度同源的结构域：第一个溴结构域（BD1）和第二个溴结构域（BD2）。Pan-BET bromodomain抑制是一种对多种癌症和免疫炎性疾病的潜在疗法，但只有极少数报道的抑制剂在BET家族中显示出选择性。在本文中，我们确定了一系列对BET BD1具有良好选择性的苯并[cd] indol-2（1H）-和吡咯并[4,3,2-de]喹啉-2（1H）-。通过基于结构的优化，最终获得了高活性和选择性的化合物。代表性化合物是最先报道的抑制剂，其对BRD4（1）的选择性超过BRD4（2）的100倍以上。他们之中，我们进一步显示68（LT052）介导具有可比蛋白质表达的BRD4 /NF-κB/ NLRP3信号传导炎症途径，并显着改善了大鼠模型中痛风性关节炎的症状。因此，对单个溴结构域的选择性药理调节可能代表了治疗急性痛风性关节炎的策略。