Bromodomains（BRDS）通过蛋白质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。BET Bromodomain已成为一个对肿瘤具有潜在治疗能力的表观遗传新靶点。在前期研究中，我们识别出BET Bromodomain存在有KAc结合区、WPF区和ZA Channel三个热点区域，其中ZA Channel是我们新发现的一个和选择性有关的热点，并且获得了一个作用于KAc结合区的先导结构片段TR_43（BRD4 IC50=2.40μM）。本项目将在前期工作的基础上，以TR_43为结构起点，运用基于片段的药物设计方法，通过对ZA Channel和WPF区适宜结构片段的发现，经过拼合进行合理的设计、化学合成，和生物活性评价，最终发现高效、高选择性的新型BET Bromodomain抑制剂，为表观遗传的抗肿瘤治疗奠定基础。

Bromodomains (BRDs) can specifically identify acetyl-lysine residues through protein-protein interactions. BRDs are present in diverse proteins that play key functions in chromatin organization and regulation of gene transcription. BET Bromodomain has become a novel epigenetic target which may have great therapeutic potential for cancers. In our preliminary study, we have identified three hot spots in BET Bromodomain, including KAc binding site, WPF shelf, and ZA Channel. Particularly, we have confirmed that ZA Channel is a key hot spot which is essential for the selectivity. Furthermore, we have obtained a promising lead fragment TR_43 (BRD4 IC50=2.40μM), which binds to the KAc site. The success of our preliminary study laid the foundation for further fragment-based drug design. Thus, in current study, we propose to identify active fragments for ZA Channel and WPF shelf by fragment-based method, and through fragment combination, chemical synthesis, and bioactivity evaluation, we expect to eventually identify potent and specific BET inhibitors as a potential avenue for epigenetic cancers.