Abstract：
Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease and lacks effective therapeutic agents. Dysregulation of transcription mediated by bromodomain and extra-terminal domain (BET) proteins containing two different bromodomains (BD1 and BD2) is an important factor in multiple diseases, including MS. Herein, we identified a series of BD1-biased inhibitors, in which compound 16 showed nanomolar potency for BD1 (Kd = 230 nM) and a 60-fold selectivity for BRD4 BD1 over BD2. The co-crystal structure of BRD4 BD1 with 16 indicated that the hydrogen bond interaction of 16 with BD1-specific Asp145 is important for BD1 selectivity. 16 showed favorable brain distribution in mice and PK properties in rats. 16 was able to inhibit microglia activation and had significant therapeutic effects on EAE mice including improvement of spinal cord inflammatory conditions and demyelination protection. Overall, these results suggest that brain-permeable BD1 inhibitors have the potential to be further investigated as therapeutic agents for MS.
摘要：
多发性硬化(MS)是一种神经炎症性自身免疫性疾病,缺乏有效的治疗药物。由含有两个不同的溴结构域（BD1和BD2）的溴结构域和末端外结构域（BET）蛋白介导的转录失调是多种疾病的重要因素。包括女士在这里，我们确定了一系列BD1偏向的抑制剂，其中化合物16显示对BD1的纳摩尔效力(Kd=230nM)和对BRD4的BD1相对于BD2的60倍选择性。BRD4BD1与16的共晶结构表明，16与BD1特异性Asp145的氢键相互作用对于BD1选择性很重要。图16显示小鼠中有利的脑分布和大鼠中的PK特性。16能够抑制小胶质细胞活化并且对EAE小鼠具有显著的治疗效果,包括改善脊髓炎症状况和脱髓鞘保护。总的来说,这些结果表明，脑渗透性BD1抑制剂有可能作为MS的治疗剂进行进一步研究。
