Bromodomains（BRDs）通过蛋白-蛋白的相互作用可特异性地识别乙酰化赖氨酸残基。BRDs存在于不同的蛋白质中，对染色质组织和基因转录调控起着关键的作用，已成为对肿瘤具有潜在治疗作用的表观遗传新靶点。而同一蛋白中不同BRDs（如BRD4蛋白中包含有BD1和BD2两个BRDs）选择性抑制剂的发现更是当前研究的主要难点和关注点。在前期研究中，我们获得了具有全新吡咯酮并喹啉骨架结构的高活性、高选择性的BRD4(BD1)的抑制剂1-21[BRD4 (BD1) IC50=34nM，BRD4 (BD2) IC50=2310nM]，其体外对四种肿瘤细胞抑制活性良好（IC50=0.16~0.99μM）。本项目拟在此基础上，以1-21为先导化合物，结合合理药物设计和类药性早期预测，对其进行结构修饰，并进行生物活性评价，为最终获得具有自主知识产权的抗肿瘤新药打下坚实的基础。

Bromodomains (BRDs) can specifically identify acetyl-lysine residues through protein-protein interactions. BRDs are present in diverse proteins that play key roles in chromatin organization and regulation of gene transcription. BET Bromodomain(bromodomain and extra C-terminal domain) has become a novel epigenetic target which may have great therapeutic potential for cancers. The discovery of selective BRDs inhibitors is an intensively studied and very challenging field. In our preliminary study, 1-21, a potent BRD4 (BD1) inhibitor [BRD4 (BD1) IC50 = 34 nM，BRD4 (BD2) IC50 = 2310 nM] with exquisite selectivity based on the novel scaffold of pyrrolo[4,3,2-de]quinolin-2(1H)-one was obtained. The molecule 1-21 exhibits potent antitumor activity in vitro with IC50 values ranging from 0.16 μM to 0.99 μM against four cancer cells. On the basis of the previous work, this project aims to optimize the lead compound 1-21 and further improve the activity by combining rational drug design and medicinal chemistry. Overall, this project will provide a solid foundation for developing novel antitumor drug candidates of independent intellectual property rights.