Discovery of Benzo[cd]indol-2(1H)-ones and Pyrrolo[4,3,2-de]quinolin-2(1H)-ones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain with Potential High Efficiency against Acute Gouty Arthritis
Discovery of Benzo[cd]indol-2(1H)-ones and Pyrrolo[4,3,2-de]quinolin-2(1H)-ones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain with Potential High Efficiency against Acute Gouty Arthritis
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发现苯并[cd]吲哚-2(1H)-酮和吡咯并[4,3,2-去]喹啉-2(1H)-酮作为溴结构域和末端结构域 (BET) 抑制剂，对第一溴结构域具有选择性
DOI：
10.1021/acs.jmedchem.9b01010
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发表时间：
2019-12-26
影响因子：
7.3
通讯作者：
Chen, Yadong
中科院分区：
文献类型：
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作者：
Jiang, Fei;Hu, Qinghua;Chen, Yadong
蛋白质的溴结构域和末端外结构域（BET）家族是特异性识别组蛋白乙酰化赖氨酸残基的阅读器。每个BET布罗莫结构域蛋白含有两个高度同源的结构域：第一布罗莫结构域（BD 1）和第二布罗莫结构域（BD 2）。Pan-BET布罗莫结构域抑制是用于各种癌症和免疫炎性疾病的潜在疗法，但只有少数报道的抑制剂在BET家族中显示出选择性。在此，我们鉴定了一系列对BET BD 1具有良好选择性的苯并[cd]吲哚-2（1H）-酮和吡咯并[4，3，2-de]喹啉-2（1H）-酮。通过基于结构的优化，最终获得高活性和选择性的化合物。代表性化合物是首次报道的抑制剂，其对BRD 4（1）的选择性超过BRD 4（2）的100倍。其中，我们进一步表明，68（LT 052）介导BRD 4/NF-κ B/NLRP 3信号传导炎症途径，具有相当的蛋白表达，并显著改善大鼠模型中痛风性关节炎的症状。因此，个体溴结构域的选择性药理学调节可以代表用于治疗急性痛风性关节炎的策略。
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-kappa B/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.