三阴性乳腺癌（TNBC）由于缺乏内分泌和靶向治疗的有效靶标，目前还没有理想的治疗药物，BRD4是TNBC治疗领域中的新靶标之一，但效价和耐药性问题尚未解决。来自基础和临床医学的最新研究表明：细胞自噬性死亡在TNBC治疗领域与BRD4抑制关系密切。我们初期工作通过整合系统生物学TCGA分析，结合分子实验首次发现BRD4和AMPK存在直接相互作用，在自噬和TNBC治疗中具有核心调控作用，经过多轮筛选，发展了通过靶向BRD4-AMPK互作诱导TNBC自噬性死亡，并显示良好的抗肿瘤效果的先导化合物FL-411。在本研究中，拟将前期得到的FL-411进行合理药物设计和化学修饰，研究其构效关系，以提高其特异性有效性。优选后化合物通过靶向BRD4-AMPK诱导TNBC自噬性细胞死亡分子机制的阐述，可为BRD4-AMPK在肿瘤治疗领域中功能研究和进一步探索创新自噬相关靶点的抗TNBC的小分子药物奠定基础。

At present, there is no ideal therapeutic drugs for triple-negative breast cancer (TNBC), because it is still lacking of effective targets for TNBC targeted therapy. BRD4 has been emerged as a novel target for TNBC targeted therapy, but effective potency and drug resistance for BRD4 inhibitors remain elusive. Recent studies have suggested that autophagic cell death is closely associated with BRD4 inhibition for the treatment of TNBC. In our previous work, we first demonstrated the potential interaction between BRD4 and AMPK by integrating system biology, TCGA analysis and co-immunoprecipitation, which is very important for breast cancer treatment. After several rounds of screening, we discovered a lead compound FL-411 targeting the PPI of BRD4-AMPK that induced autophagic cell death and showed good anti-tumor effects in vivo. In this study, we proposed to carry out rational drug design and chemical modification based upon the lead compound FL-411, as well as illuminate its structure-activity relationship and improve its specificity and efficacy. This study will illustrate the molecular mechanisms of optimized compound, which would provide foundations for the functional research of BRD4-AMPK interaction in cancer therapy as well as the exploration of anti-TNBC drugs based on autophagic target.