Sepsis has long been a major health problem worldwide. It threatens the lives of hospitalized patients and has been one of the leading causes of death in hospitalized patients over the past decades. BRD4 has been regarded as a potential target for sepsis therapy, for its critical role in the transcriptional expression of NF-κB pathway-dependent inflammatory factors. In this study, compound 1 was obtained through virtual screening, and candidate compound 27 was obtained through several rounds of iterative SAR analysis. 27 decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1β and TNF-α. In vivo, 27 effectively protected mice from LPS-induced sepsis, increased survival rate and decreased the level of pro-inflammatory factors in serum. Collectively, we reported here 27, a BRD4 inhibitor with a new scaffold, as a potential candidate for the treatment of sepsis.

脓毒症长期以来一直是世界范围内的主要健康问题。它威胁着住院患者的生命，并且在过去几十年中一直是住院患者死亡的主要原因之一。BRD4 被认为是脓毒症治疗的潜在靶点，因为它在 NF-κB 通路依赖性炎症因子的转录表达中起关键作用。本研究通过虚拟筛选获得化合物1 ，通过多轮迭代SAR分析获得候选化合物27 。27减少 LPS 诱导的 NO 产生和促炎因子 IL-6、IL-1β 和 TNF-α 的表达。体内，27有效保护小鼠免受 LPS 诱导的脓毒症，提高存活率并降低血清中促炎因子的水平。总的来说，我们在这里报道了27，一种带有新支架的 BRD4 抑制剂，作为治疗败血症的潜在候选者。