肽类蛋白酶体抑制剂的研究已取得了显著进展，但此类抑制剂存在毒副作用大、对实体瘤抑制率低和代谢稳定性不好等缺点。非肽类小分子蛋白酶体抑制剂有望克服肽类蛋白酶体抑制剂的这些缺点。因此，本课题将依据我们前期的研究结果，结合蛋白酶体抑制剂研究的最新进展，选择优秀的氨基硼酸和噁二唑为靶头，四氢异喹啉、多芳基取代吡唑、芳基磺酰胺为活性片段，借助于计算机辅助药物设计筛选出适当的连接臂将其连接，设计、合成五类非肽类小分子蛋白酶体抑制剂（I-V）；在酶和细胞两个水平上评价其活性，总结其构效关系；选择活性好的化合物进行体内活性评价，及初步药代动力学和急性毒性研究，以期发现优秀的非肽类小分子蛋白酶体抑制剂，开辟非肽类蛋白酶体抑制剂研究的新方向。

The study of peptide proteasome inhibitors has made great progress. However, this kind of drugs has some significant shortcomings, such as high toxicities, lack of efficacy in solid cancer patient and poor in vivo stability et al.. Non-peptide small molecular proteasome inhibitor may be one of an efficient route to overcome these shortcomings. Thus, five kinds of non-peptide small molecular proteasome inhibitors (I-V) will be designed and synthesized in this project based on the combination of our previous research results and the latest advances of proteasome inhibitor. We selected alpha-aminoboronic acid and oxadiazole as warhead, and tetrahydroisoquinoline, diaryl pyrazole and N-aryl sulfonamide as active fragments, which are linked into target compounds（I-V）through the suitable linkers. The suitable linkers will be obtained by the aid of computer aided drug design. All the target compounds will be evaluated for their activities against proteasome and tumor cells, and their structure-activities relationships will be summarized. The promising compounds will be further evaluated for their in vivo antitumor activities, PK properties and acute toxicity. Our goal is to find more potential proteasome inhibitors and open the new research direction of non-peptide small molecular proteasome inhibitors.