新型双功能抗肿瘤药物蛋白酶体抑制剂的设计、合成及优化

The Ubiquitin-Proteasome Pathway (UPP) plays a vital role in replication and proliferation of tumors, whereas selective blockage of the UPP enables efficient prevention of the reproduction of various tumors. In this proposal, we focus on the 20S proteasome, the core component of the UPP, as our target. By using available crystal structure of the proteasome-inhibitor complexes, we plan to design novel bifunctional lead compounds, which bear both proteasomal-inhibitive ability and fluorescent emission. Subsequent delicate synthesis, biological evaluation, mechanistic clarification and intentional optimization of the molecular structure aided by CADD, can help us investigate the dynamic bonding process between the inhibitors and the target, and provide us more information about the transformation of molecular structure and biological function of the proteasome and its subunits. On the other hand, study of the proteasome inhibitors as fluorescent probe can help us learn more about the impact of replication and proliferation of the tumors mediated by the UPP. In summary, we aim to discover a certain amount of lead structure of novel proteasome inhibitors, to expand the scope of current structure of proteasome inhibitors, to improve the pharmacokinetic and pharmacological properties, and finally, to establish the foundation for creation of anti-tumor agents based on novel mechanism and advantages such as high safety and selectivity, low toxicity and drug-resistance.

泛素-蛋白酶体通路在肿瘤复制和增殖过程中发挥着重要作用，选择性阻断此通路可有效阻止多种肿瘤的繁殖。本项目以泛素-蛋白酶体通路的核心-20S蛋白酶体为靶点，从蛋白酶体-抑制剂复合物晶体结构出发，设计结构新颖的具有蛋白酶体抑制活性和荧光发光性质的双功能先导化合物，并对目标分子进行化学合成、生物作用评价、机制阐明，并且综合运用各种计算机辅助药物设计技术进行构效关系分析及结构优化。研究抑制剂与靶点结合前后蛋白酶体及其亚基的分子结构和生物功能的变化，并且通过抑制剂分子的荧光来监测由此导致的泛素-蛋白酶体通路的抑制作用对肿瘤细胞复制和增殖的影响。目的在于发现多个新颖的蛋白酶体抑制剂先导结构，丰富现有抑制剂结构类型，同时改善药动学、药效学性质，为创制具有安全性高、毒性低、不易产生耐药性、特异性高等特点的新作用机制的抗肿瘤药物奠定基础。

泛素-蛋白酶体通路在肿瘤复制和增殖过程中发挥着重要作用，选择性阻断此通路可有效阻止多种肿瘤的繁殖。本项目以泛素-蛋白酶体通路的核心-20S蛋白酶体为靶点，从蛋白酶体-抑制剂复合物晶体结构出发，设计结构新颖的具有蛋白酶体抑制活性和荧光发光性质的双功能先导化合物，并对目标分子进行化学合成、生物作用评价、机制阐明，并且综合运用各种计算机辅助药物设计技术进行构效关系分析及结构优化。研究抑制剂与靶点结合前后蛋白酶体及其亚基的分子结构和生物功能的变化，并且通过抑制剂分子的荧光来监测由此导致的泛素-蛋白酶体通路的抑制作用对肿瘤细胞复制和增殖的影响。目的在于发现多个新颖的蛋白酶体抑制剂先导结构，丰富现有抑制剂结构类型，同时改善药动学、药效学性质，为创制具有安全性高、毒性低、不易产生耐药性、特异性高等特点的新作用机制的抗肿瘤药物奠定基础。