靶向FAK/PLK1双靶点抑制剂的发现与抗肿瘤转移活性研究

黏着斑激酶（FAK）在肿瘤发育到远端转移的过程中发挥着重要作用，然而临床面临疗效不显著、不良反应严重等难题，至今未有FAK抑制剂被批准上市。同时，基于Polo样激酶1（PLK1）与FAK在肿瘤发生发展过程中存在重要的交叉影响，我们提出假设：开发针对FAK/PLK1的双靶点抑制剂用于抗肿瘤药物极有可能在抗肿瘤转移方面取得重要进展。本课题基于前期工作基础，通过分析FAK和PLK1与各自配体的晶体结构，结合3D药效团指纹、电子势能等各种参数构建药效团模型，筛选活性骨架与活性位点对接，构建3D-QSAR模型开展新型FAK/PLK1双靶点抑制剂的发现与优化研究，同时采用蛋白免疫印迹、乳腺癌T47DSCID小鼠移植瘤模型等方法进行药效学评价研究，期望得到1-2个新型高效FAK/PLK1双靶点抑制剂用于抗肿瘤候选药物，从生物化学、分子生物学层面阐述其抗肿瘤作用机制，克服现有恶性肿瘤转移难题。

Focal adhesion kinase (FAK) plays an important role in tumor development and metastasis. However, there are some problems in the process of clinical use, such as no significant effect, serious adverse reactions, etc. So far, there is no FAK inhibitor approved for marketing. Polo-like kinase 1 (PLK1) and FAK have a wide range of cross effects in tumor genesis and tumor development. Therefore, the development of dual inhibitor of FAK/PLK1 is likely to make positive progress in anti-tumor metastasis. Based on our previous study and the complexes of FAK and PLK1 and their ligands, skeletons could be obtained by analyzing the similarity and difference of different ligands in terms of 3D pharmacophore fingerprints, strain energy and electronic potential energy. 3D-QSAR could be therefore designed by docking the skeletons within the active sites of FAK and PLK1 complexes, thus providing a new theoretical basis and method for rational drug design. At the same time, Western-blot and breast cancer T47d SCID mice transplanted tumor model were used to evaluate the pharmacodynamics. We expect to get 1-2 dual FAK/PLK1 inhibitors with high efficiency and low toxicity to overcome the tumor metastasis, and explain the mechanism of anti-tumor action from biochemical and molecular biological level.