BET Bromodomain抑制剂作用机制清晰明确，有可靠的成药性基础，目前已有11个BET Bromodomain抑制剂正在进行临床试验。随着临床研究的深入， BET Bromodomain抑制剂诱导的耐药性成为亟需解决的问题。本项目的主要目标是开发一类新颖的、含有苯一氮䓬结构的BET Bromodomain小分子抑制剂，获得具有优异体内外活性、良好安全性的临床候选药物分子。在此基础上，开发一类新颖的分子探针，定向诱导细胞和动物体内的BET蛋白高效降解。在对BET Bromodomain抑制剂具有耐药性或不敏感的肿瘤细胞株内，深入研究促进BET蛋白降解和细胞活性之间的关系。优化这类分子探针在动物体内的药代动力学性质、安全性和药效，探索解决BET Bromodomain抑制剂耐药性问题的新途径。

The BET Bromodomain is a good drug target and the mechanism of action of its inhibitors is clear and predictable. So far, there are eleven inhibitors of BET Bromodomain (BET inhibitors) that are being studied in human clinical trials. As the clinical trials move forwards, drug resistance of the inhibitors are emerging and has received considerable attention from both pharmaceutical companies and academic labs. The objective of this proposal is to develop a class of novel small-molecule BET inhibitors featuring benzoazepine structure. Upon optimization, we are intended to obtain drug candidates with optimal in vitro and in vivo efficacy and safety profiles. In addition, we will develop a class of novel chemical probes that induce significant degradation of BET proteins in vitro and in vivo. The relationship between degradation of BET proteins and cellular activity in cancer cell lines that are resistant or insensitive to BET inhibitors will be carefully studies. The pharmacokinetics, toxicity and efficacy of the chemical probes will be optimized in order to explore the opportunity to overcome drug resistance associated with the BET inhibitors.