具有ABC转运蛋白抑制功能的新型EGFR抑制剂的分子构建及作用机制研究

Tumour is the most common cancer with high incidence. However, the resistance can easily be observed after a period of treatment using traditional chemotherapeutic drugs and molecular-targeted kinase inhibitors. The recent study provided EGFR inhibitors, such as Erlotinib, could perform as the substrate and be pumped out of the cells by ABC transporters, then lead to resistance in the therapeutic dose, while as the inhibiter of ABC transporter in high doses. In this study, with regards to structural characteristics of ABC transporters and their drug efflux mechanism, rational methods including bioisostere, pharmacophore combination/ replacement scaffold hopping were recruited in drug design. The advantage active moieties of ABC transporter inhibitors were introduced into EGFR inhibitors. Then comprehensive evaluation of the target compounds was conducted to explore the balance between inhibitory effect on ABC transporters and itself kinase inhibitory activity. Finally, the preferred candidates at therapeutic dose can also play the reversing multidrug resistance activity. Finally, the optimal compounds will eventually evaluated in the mechanism of action, and the the effect of different side chain structure on the inhibitory activity of ABC transporter and EGFR would be summarized. Generally, It is expected that EGFR targeted therapy with potent ABC-transporter inhibitory activity would provide a theoretical basis for the development of cancer has developed resistance and has maladjustment of epidermal growth factor expression.

肿瘤在使用传统化疗药物和分子靶向的激酶抑制剂治疗一段时间后，均易产生耐药现象。新研究发现厄洛替尼等EGFR抑制剂治疗剂量下可被ABC转运蛋白外排出肿瘤细胞，产生多药耐药现象；但高剂量时又能抑制ABC转运蛋白功能。本课题拟基于ABC转运蛋白介导的药物外排机制及其结构特点，进行合理药物设计，将ABC转运蛋白抑制剂的优势活性片段引入EGFR抑制剂结构中，对目标化合物进行全面的活性筛选，期望提高化合物的对ABC转运蛋白的抑制活性，在激酶治疗剂量时即可同时发挥逆转多药耐药的功能。对优选化合物进行深入的作用机制研究，并分析化合物的不同侧链结构对ABC转运蛋白和EGFR抑制活性的影响，总结构效关系。获得具有强效ABC转运蛋白抑制活性的EGFR靶向治疗药物，为已耐药的EGFR表达失调的肿瘤的新型治疗药物研究与开发奠定坚实的理论基础。

肿瘤在使用传统化疗药物和分子靶向的激酶抑制剂治疗一段时间后，均易产生耐药现象。新研究发现厄洛替尼等EGFR抑制剂治疗剂量下可被ABC转运蛋白外排出肿瘤细胞，产生多药耐药现象；但高剂量时又能抑制ABC转运蛋白功能。本课题基于ABC转运蛋白介导的药物外排机制及其结构特点，进行合理药物设计，通过引入色酮结构片段和嘧啶氨基苯结构片段，降低化合物刚性，电子等排原理，仲胺修饰酰胺键及用click化学方法，共计设计合成得到了VI类化合物57个，结构和纯度经质谱和高效液相色谱分析确证。在正常敏感细胞株和对应耐药株上对所有目标化合物进行了体外细胞毒性测试，在耐药细胞株上全面评估了目标化合物对ABC转运蛋白的抑制活性。对优选化合物进行了在不同的ABC 转运蛋白和EGFR 高表达的细胞细胞系上进行深入的整体动物和细胞分子机制研究，并分析化合物的不同侧链结构对ABC转运蛋白和EGFR抑制活性的影响，总结构效关系，深入揭示了ABC 转运蛋白和EGFR 共同抑制后的体内外抗肿瘤的协同增效机制。为已耐药的EGFR表达失调的肿瘤的新型治疗药物研究与开发奠定坚实的理论基础。