基于蛋白-蛋白相互作用精准调节转录因子Nrf2活性及探索其作为肝细胞癌治疗的新靶标

转录因子是控制基因表达的重要分子，在体内发挥重要的生物学功能，其活性受到严密和精细的调节。转录因子的异常活化在恶性肿瘤发生发展中扮演重要作用。本项目以转录因子Nrf2为研究对象，针对Nrf2异常活化在肝细胞癌中的核心促癌作用，开发特异性Nrf2抑制剂。本项目创新性的提出“基于蛋白-蛋白相互作用正常化转录因子Nrf2的泛素化系统”的新策略，另辟蹊径通过化学小分子选择性抑制Keap1-p62蛋白-蛋白相互作用，恢复体内泛素E3连接酶Keap1对Nrf2的活性，促进Nrf2泛素化降解，达到特异性和适度调控肝细胞癌内异常升高的Nrf2活性而不影响Nrf2正常生理功能的目的，实现对肝细胞癌的选择性杀伤。本项目的研究一方面可探索靶向化学干预Nrf2活性在肝细胞癌治疗中的应用；另一方面为转录因子活性调节提供了全新思路，可成为转录因子调节剂发现的新策略。

Transcription factors are the key regulators of gene transcription, which play important roles in the human body. The abnormal regulation of transcription factor is an important factor for multiple complex diseases, especially cancer. In this project, we focus on the development of the therpuatic agents targeting transcription factor Nrf2. The abnormal activation of Nrf2 contributes a lot to the occurrence and progress of hepatocellular carcinoma. We proposed the new thoughts of targeting the abnormal regulation of transcription factor ubiquitination by small molecule protein-protein interaction inhibitors and put forward the method of normalization the function of ubiquitin E3 ligase Keap1 to regulate Nrf2 ubiquitination. By selectively targeting Keap1-p62 protein-protein interaction, the key node of the abnormal ubiquitination regulation of Nrf2, the small molecules can recover the activity of E3 ligase Keap1 and ubiquitinates Nrf2 normally. These agents will be further explored in the therapy of hepatocellular carcinoma. This research not only can provide new chemical tools to elucidate the possibility of Nrf2 inhibition in HCC therapy, but also give new insights into the discovery of therpuatic agents targeting transcription factor.