自噬关键激酶ULK1作为肝细胞癌药物治疗新靶点的系统研究

肝细胞癌（HCC）治疗手段严重不足，寻找新药靶至关重要。近年来自噬与肿瘤关系逐步被揭示：HCC自噬上调并影响预后；索拉非尼激活自噬诱发耐药；ULK1介导自噬激活与耐药相关。揭示“自噬，HCC，耐药，ULK1”的相关性。ULK1作为自噬启动因子，结构上是自噬通路中唯一可能成为药靶的蛋白。申请人前期工作发现沉默或敲除ULK1抑制了HCC增殖，增效索拉非尼。初筛发现ULK1抑制剂XST-14下调自噬并抗HCC。鉴于自噬调节通路与HCC治疗的重要关系，本项目拟通过药物化学生物学的方法，探索ULK1作为HCC新药靶的可能，首先明确ULK1在HCC中的生物学功能，之后寻找特异性抑制剂为工具分子，阐明ULK1作为药靶的机制依据，治疗价值及安全性，并开展药物发现研究。ULK1作为药靶是治疗HCC的全新策略，单用疗效可期，联用具有抵抗索拉非尼耐药，提升患者PFS和OS的可能。研究科学意义与潜在临床价值较大。

Treatments for hepatocellular carcinoma (HCC) are woefully inadequate, making the search of new drug targets crucial. In recent years, the relationship between autophagy and tumor has been clarified step by step: HCC autophagy could up-regulate and influence prognosis; sorafenib could activate autophagy and induce drug resistance; ULK1 - mediated autophagy activation was related to drug resistance. Meanwhile, the correlation of “autophagy, HCC, drug resistance and ULK1” has also been revealed. ULK1, as an autophagy initiator, was structurally the only potential drug target protein in the autophagic pathway. The applicant found in the preliminary research that silencing or knocking out ULK1 inhibited HCC proliferation and enhanced the effect of sorafenib. According to preliminary screening, ULK1 inhibitor XST-14 down-regulated autophagy and resisted against HCC. In view of the important relationship between autophagy regulation pathways and HCC treatment, this project plans to explore the possibility of ULK1 being a new drug target for HCC based on chemical biological methods: first, define the biological function of ULK1 in HCC; then, search for specific inhibitors as tool molecules; clarify the mechanism of taking ULK1 as a drug target, its therapeutic value and safety, and proceed with drug discovery research. ULK1 being a drug target is a new strategy for HCC treatment. When used alone, it shows a promising effect; when used with other drugs, it is against sorafenib drug resistance and in favor of a higher PFS and OS in patients. The research is therefore of greater scientific significance and potential clinical value.