Discovery of a Bromodomain and Extra Terminal Domain (BET) Inhibitor with the Selectivity for the Second Bromodomain (BD2) and the Capacity for the Treatment of Inflammatory Diseases

Selectiveinhibitors targeting the first bromodomain (BD1) or thesecond bromodomain (BD2) of the bromodomain and extra terminal domain(BET) proteins have triggered extensive research to produce more specificagents. Herein, we described our efforts to design and synthesizea series of selective BET BD2 inhibitors with novel structures. Amongthem, compound 45 showed single-digit nanomolar potencyagainst BRD4 BD2 (IC50: 1.6 nM) and a 328-fold selectivityfor BRD4 BD2 over BRD4 BD1 (IC50: 524 nM). Besides, 45 possessed potent effects on regulating the differentiationof Th17 cells and reducing the levels of Th17-related cytokines byaffecting the activation of STAT3 and NF-& kappa;B. Further studiesdemonstrated that 45 had significant therapeutic efficacyin mouse models of imiquimod (IMQ)-induced psoriasis and dextran sulfatesodium (DSS)-induced inflammatory bowel disease (IBD). This work providesa strong foundation for the development of selective BET BD2 inhibitorsand the therapeutic strategy for psoriasis and IBD.