BRD4蛋白抑制剂/降解剂的设计、合成及抗肝纤维化研究

Liver fibrosis, characterized by excessive accumulation of extracellular matrix proteins, is one of the major causes of morbidity and mortality worldwide. Despite a few anti-fibrotic therapies for liver diseases have entered clinical trials, no drug has been approved for the treatment of liver fibrosis. BRD4 from BET family has been identified as the key regulator of liver fibrosis and is therefore a potential target for developing anti-liver fibrosis drugs. In this proposal, structure-based drug design (SBDD) and computational docking will be employed to design novel BRD4 inhibitors, leading to generation of lead compounds with different pharmacological profiles. This will further exploit the therapeutic potential of BRD4 inhibition in different human diseases. Based on these inhibitors with different chemotypes, BRD4 degraders will be designed and synthesized by utilizing a PROTAC technology. These bifunctional PROTAC molecules may mitigate the potential drug-resistance and toxicity risks associated with BRD4 inhibitors. The anti-fibrotic effect of selected BRD4 inhibitors and degraders will be assessed in the carbon tetrachloride-induced mouse model. This will lay solid foundation for the development of safe and effective anti-fibrotic drugs for liver.

肝纤维化是严重威胁人类健康和生存的慢性肝脏疾病，目前尚无治疗药物上市。BET家族的BRD4蛋白是肝纤维化的重要调控因子，对其抑制能有效缓解肝纤维化进程，因而成为抗肝纤维化的潜在靶点。本项目拟通过基于结构的药物设计和分子对接的方法，寻找和发现具有新颖结构的BRD4抑制剂，丰富现有抑制剂的化学结构多样性，得到具有不同药理的先导化合物，以拓展该靶点在不同疾病领域的应用。在此基础上，设计与合成基于PROTAC技术的BRD4降解剂，以解决BRD4抑制剂潜在的耐药性和安全性风险，更加符合慢性疾病治疗药物在该方面的严苛要求。以四氯化碳诱导的小鼠作为动物肝纤维化模型，测试所筛选出的BRD4抑制剂和降解剂的抗肝纤维化药效，为进一步开发安全有效的抗肝纤维化药物奠定良好的基础。

含溴结构域蛋白4（BRD4）通过识别组蛋白乙酰化赖氨酸并与之结合，招募染色质调控因子，促进下游基因转录。因此，BRD4蛋白的异常与多种疾病的发生发展密切相关，是潜在的疾病治疗靶点。. 我们通过计算机辅助药物设计和合理药物设计理念，获得了近80个具有全新骨架的BRD4抑制剂，该类化合物对BRD4蛋白的两个溴结构域（BD1和BD2）均表现出优良的酶抑制活性，且也显示良好的体外抗肿瘤活性。紧接着，我们又设计与合成了60余个高BD2选择性的BRD4抑制剂，优选化合物具有良好的体内外抗肿瘤效果，且比阳性药具有更高的hERG安全性。同时，又设计与合成了约30个SHP2/CDK4双靶点抑制剂，候选化合物具有优异的体内外抗肿瘤活性。. 基于这些研究，发表相关的SCI论文6篇，申请发明专利5项，获授权专利1项，协助培养了1名青年教师、2名博士研究生和4名硕士研究生。