三阴性乳腺癌的高死亡率已成为其治疗中的一大难题, 尽管目前临床上有一些用于治疗三阴性乳腺癌的药物，但患者的远期生存率未得到明显改善；所以阐明三阴性乳腺癌的重要机制, 并基于此寻找新的治疗靶点具有重要的意义。最新研究表明细胞自噬在三阴性乳腺癌中发挥重要作用。在前期工作中, 我们发现自噬中关键分子eEF2K可能是干预三阴性乳腺癌的潜在靶点。我们设计合成了靶向eEF2K的小分子抑制剂, 发现了新化合物SKLB-EKI03能抑制保护性自噬并诱导细胞凋亡，对三阴性乳腺癌具有很好的治疗潜力。以此为基础, 本项目拟阐明化合物SKLB-EKI03对自噬分子eEF2K的靶向性及专一性，明确其在三阴性乳腺癌体内外调控eEF2K-ULK1的自噬通路及诱导凋亡的分子机制。本研究将有助于确认SKLB-EKI03是否作为抗肿瘤特异性靶向化合物及其作用基础,为开发新型靶向抗三阴性乳腺癌小分子药物提供新思路。

High mortality rate of triple-negative breast cancer (TNBC) is a major challenge of breast cancer therapy. Although there are some clinical drugs used to treat TNBC, resulting in no significant improvement of long-term survival rates. Therefore, elucidating molecular mechanisms of TNBC is of great concern for the discovery of novel therapeutic targets and thus prolonging survival rates of patients. Recent studies have reported that autophagy plays a key role in TNBC progression. In our previous studies, we discovered the key autophagic modulators eEF2K would be a potential target of TNBC. In addition, we designed and synthesized series of small-molecule inhibitors of eEF2K. After several rounds of screening, we discovered a novel compound named SKLB-EKI03 that inhibited autophagy, thus inducing apoptosis in TNBC, which shows therapeutic potential in TNBC treatment. Therefore, in this study, we will illuminate the targeted selectivity and specificity of SKLB-EKI03 to eEF2K, and elaborate the intricate mechanisms of eEF2K regulated cytoprotective autophagy and apoptosis, as well as their relations in TNBC. Together, these findings will provide a theoretical foundation for the development of a potential anti-tumor drug targeting this autophagic regulator eEF2K for the future TNBC therapy.