Bromodomain-containing protein 4 (BRD4), an epigenetic reader, is recognized as a potential therapeutic target for several types of cancer and cardiovascular diseases. In this study, a series of 1,7-dibenzyl-substituted theophylline derivatives were synthesized and their BRD4 inhibitor activities were evaluated. Most of the compounds showed detectable activities with IC₅₀ values in the range 2.51–10.50 µM. Therein, compound 16d showed significant selectivity for two bromodomains of BRD4, where the inhibition of BD1 (IC₅₀ = 2.51 µM) was 20-times greater than that of BD2 (IC₅₀ > 50 µM). Similarly, compounds 16a–16c, 16e, 16h, and 18c also displayed favorable BRD4-BD1 selectivity. In addition, molecular docking of compound 16d was performed to predict it binding pattern with BRD4, indicating that residue Ile146 is crucial to the observed selectivity of BRD4-BD1. These findings will be of great value and significance for the development of novel BRD4-BD1 inhibitors.

含有溴结构域的蛋白质4（BRD4）是一种表观遗传阅读器，被认为是几种癌症和心血管疾病的潜在治疗靶标。在这项研究中，合成了一系列的1,7-二苄基取代的茶碱衍生物，并评估了其BRD4抑制剂的活性。大多数化合物显示出可检测的活性，IC ₅₀值在2.51–10.50 µM的范围内。其中，化合物16d对BRD4的两个溴结构域显示出显着的选择性，其中BD1的抑制作用（IC ₅₀  = 2.51 µM）比BD2的抑制作用大20倍（IC ₅₀  > 50 µM）。同样，化合物16a – 16c，16e，16h和18c还显示出良好的BRD4-BD1选择性。另外，进行化合物16d的分子对接以预测其与BRD4的结合模式，表明残基Ile146对观察到的BRD4-BD1的选择性至关重要。这些发现对于开发新型的BRD4-BD1抑制剂具有重要的价值和意义。