癌干细胞同时具有自我更新和分化能力，在维持恶性增殖，侵袭，转移和复发能力方面发挥了决定性作用，往往对化疗药物、辐射等又具有较强的抗性。要彻底医治肿瘤,就需根除癌干细胞。目前已有多种FAK或者Src激酶抑制剂作为抗肿瘤药,进入临床前和临床研究,并显示出可喜的成果。在前期研究中，基于FAK激酶活性部位结构,设计合成了两个新系列的抑制剂,它们具有良好的抗肿瘤生长、转移和抗血管生成活性。由于FAK/Src激酶信号传导具有调节癌干细胞的功能,因此本项目拟基于两个激酶活性部位的结构,合成FAK/Src激酶双重抑制剂,用于杀伤癌干细胞,以达到从根本上治愈肿瘤的目的。项目设计将从三个不同芳香杂环的骨架，引入能与两个激酶相互作用的特征片段，通过分子模拟对接，优化分子结构，合成新型双重抑制剂，研究其构效关系、抗癌干细胞作用及机理。纳米粒子治疗靶向递送系统的研发将能定点传递药物,提高药物抗癌功效。

Cancer stem cells (CSCs) have the capability of both self-renewal and differentiation into diverse cancer cells, which play a decisive role in maintaining capacity for malignant proliferation, invasion, metastasis, and tumor recurrence. In order to completely cure cancer, we need to eradicate the cancer stem cells. Some inhibitors of FAK and Src kinases have been currently in preclinical and clinical development as anti-cancer agents and shown promising results. In the previous research, based on the structure of the catalytic site of FAK, we have designed and synthesized two new families of FAK inhibitors, which showed anti-angiogenic, anti-tumor and anti-metastatic activity to a variety of tumors. Since FAK/Src kinase signaling pathways can regulate cancer stem cell functions, this proposal thus plans to research for novel dual inhibitors of FAK/Src kinases using the structural information obtained through the X-ray crystallography of both FAK and Src kinases, in order to kill cancer stem cells and completely cure tumors. The proposal will design with the assistance of molecular docking to introduce characteristic fragments able to interact with the catalytic site of two kinases to three different aromatic heterocyclic skeletons, synthesize novel dual inhibitors of FAK/Src kinases and investigate structure-activity relationship as well as their roles and mechanisms of the anti-cancer stem cells. The development of targeted delivery system of therapeutic nanoparticles will provide accurate in vivo tumor targeting, and improved anti-cancer efficacy for dual inhibitors of FAK/Src kinases.