Design, synthesis, biological evaluation, and molecular docking of 1,7-dibenzyl-substituted theophylline derivatives as novel BRD4-BD1-selective inhibitors

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 IC 50 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 (IC 50 = 2.51 µM) was 20-times greater than that of BD2 (IC 50 > 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.