Department of Medicinal Chemistry , University of Minnesota , 2231 6th Street SE , Minneapolis , Minnesota 55455 , United States.
Department of Chemistry , University of Minnesota , 207 Pleasant Street SE , Minneapolis , Minnesota 55455 , United States.
J Med Chem. 2018 Oct 25;61(20):9316-9334. doi: 10.1021/acs.jmedchem.8b01248. Epub 2018 Oct 16.
As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ε-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.
作为转录的调控因子，能够识别组蛋白 N 端尾部翻译后修饰的表观遗传蛋白对于维持细胞内稳态至关重要。当这些“读取器”蛋白失调时，就会成为疾病的驱动因素。在溴结构域中，它可以识别 N-ε-乙酰化赖氨酸，对单个溴结构域和额外末端（BET）家族溴结构域的选择性抑制一直具有挑战性。我们描述了 N 端 BET 溴结构域的选择性大于 55 倍的 1,4,5-三取代咪唑双激酶-溴结构域抑制剂。BRD4N 端溴结构域（BRD4(1)）相对于其第二个溴结构域（BRD4(2)）的选择性源于有序水的置换和 BRD4(1)中赖氨酸-141 的构象灵活性。通过降低 c-Myc 表达、抑制 NF-κB 信号以及通过潜在的协同抑制 BRD4(1)和 p38α 来抑制 IL-8 产生，证明了其细胞功效。这些双抑制剂为 BRD4 的结构域选择性抑制提供了一个新的支架，BRD4 的异常功能在癌症和炎症信号中起着关键作用。
