Development of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as a novel chemical series of BRD4 inhibitors

Bromodomain protein 4 (BRD4) is a member of the bromodomain and extra-terminal domain (BET) protein family. It binds to acetylated histones that regulate gene transcription preferentially at super-enhancer regions. Now BRD4 has been involved into several types of cancers as a candidate correlated with gene transcription. In this study, we designed and synthesized 11 novel 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives and evaluated their BRD4 inhibitory activities. Most of these compounds exhibited moderate BRD4 inhibitory activities in vitro. It is worth noting that compound 14a showed excellent BRD4(1) and BRD4(2) inhibitory activity with IC50 values of 350 and 290 nm, respectively. Meanwhile, remarkable anti-proliferative activities toward BRD4-sensitive cancer lines MV4-11 and HL-60 were also observed. In addition, molecular docking studies was utilized to elaborate the key interactions between compound 14a and BRD4 in detail. Overall, 7-methylimidazo[1,5-a]pyrazin-8(7H)-one could be employed as a useful scaffold toward more potent BRD4 inhibitors for cancer treatments.