Bromodomain and extra-terminal domain (BET) protein plays an important role in epigenetic regulation, and the regulation of disruption contributes to the pathogenesis of cancer and inflammatory disease. With the goal of discovering novel BET inhibitors, especially BRD4 inhibitors, we designed and synthesized several compounds starting from our previously reported pyrido-benzodiazepinone derivative 4 to enhance BRD4 inhibitory activity while avoiding hERG inhibition. Molecular docking studies and structure–activity relationship studies led to the identification of 9-fluorobenzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivative 43, which exhibited potent BRD4 inhibitory activity with excellent potency in imiquimod-induced psoriasis model mice.

Bromodomain and extra-terminal domain (BET) 蛋白在表观遗传调控中起着重要作用，破坏的调控有助于癌症和炎症性疾病的发病机制。为了发现新的 BET 抑制剂，尤其是 BRD4 抑制剂，我们从我们之前报道的吡啶并苯二氮卓酮衍生物4开始设计并合成了几种化合物，以增强 BRD4 抑制活性，同时避免 hERG 抑制。分子对接研究和结构-活性关系研究导致鉴定了 9-氟苯并[ f ]吡啶并[4,3-b][1,4]oxazep​​in-10-one衍生物43，其表现出强大的BRD4抑制活性和优异的效力在咪喹莫特诱导的银屑病模型小鼠中。