Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, Arkansas 72205, United States.
J Med Chem. 2021 Jul 22;64(14):10497-10511. doi: 10.1021/acs.jmedchem.1c00933. Epub 2021 Jul 8.
The bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and D2. The protein-protein interactions between BET bromodomains, acetylated histones, and transcription factors are therapeutic targets for BET-related diseases, including inflammatory disease and cancer. Prior work demonstrated that methylated-1,2,3-triazoles are suitable -acetyl lysine mimetics for BET inhibition. Here we describe a structure-activity relationship study of triazole-based inhibitors that improve affinity, D1 selectivity, and microsomal stability. These outcomes were accomplished by targeting a nonconserved residue, Asp144 and a conserved residue, Met149, on BRD4 D1. The lead inhibitors and have a BRD4 D1 of 12 and 6.4 nM, respectively. Cellular activity was demonstrated through suppression of c-Myc expression in MM.1S cells and downregulation of IL-8 in TNF-α-stimulated A549 cells. These data indicate that and are new leads to investigate the anticancer and anti-inflammatory activity of BET proteins.
溴结构域和末端结构域（BET）蛋白家族使用两个 N 端溴结构域 D1 和 D2 识别组蛋白和转录因子中的乙酰化赖氨酸。BET 溴结构域、乙酰化组蛋白和转录因子之间的蛋白-蛋白相互作用是 BET 相关疾病（包括炎症性疾病和癌症）的治疗靶点。先前的工作表明，甲基-1,2,3-三唑是 BET 抑制的合适乙酰化赖氨酸类似物。在这里，我们描述了基于三唑的抑制剂的构效关系研究，这些抑制剂提高了亲和力、D1 选择性和微粒体稳定性。通过靶向 BRD4 D1 上的非保守残基 Asp144 和保守残基 Met149 来实现这些结果。先导抑制剂 和 的 BRD4 D1 值分别为 12 和 6.4 nM。通过在 MM.1S 细胞中抑制 c-Myc 表达和在 TNF-α 刺激的 A549 细胞中下调 IL-8 来证明细胞活性。这些数据表明 和 是研究 BET 蛋白的抗癌和抗炎活性的新先导化合物。
