蛋白酶体是经临床验证的抗肿瘤药物靶点。由于组成型蛋白酶体与机体的正常生理功能密切相关，选择性抑制免疫蛋白酶体有可能避免毒性反应，是更合理的靶向抗肿瘤药物设计策略。本项目拟基于免疫蛋白酶体的结构生物学研究进展，针对抑制剂结构中对亚基选择性敏感的分子区域，采用基于片段的设计策略，并结合基于结构的分子设计技术及骨架迁越策略，来充分探查抑制剂化学结构与亚型选择性抑制作用的构效关系，寻找和发现结构新颖的非共价结合型选择性免疫蛋白酶体抑制剂，并探究选择性免疫蛋白酶体抑制作用对于抑制剂作为潜在抗肿瘤治疗药物的药效和毒性作用特点的影响。选择性免疫蛋白酶体抑制剂的发现不仅有利于采用化学生物学手段，阐明各免疫蛋白酶体亚基的生物学功能，而且有助于运用药物化学手段，揭示免疫蛋白酶体选择性抑制作用对于抑制剂作为肿瘤、炎症和自身免疫性疾病等治疗药物成药性特征的影响。

Proteasome is a clinically validated target for anticancer drugs. Since constitutive proteasome is intensely involved in physiological processes, it might be a better strategy for cancer therapy to selectively target immunoproteasome so as to avoid systematic toxicity. Based on the structural biology achievements on immunoproteasome, an integrated approach combining fragment-based drug design, structure-based drug design and scaffold hopping techniques has been proposed herein. It aims to identify novel, non-covalent and selective inhibitors for human immunoproteasome through efficient and adequate exploration on structure-activity relationships. The effects of selective inhibition against human immunoproteasome on the activity and toxicity profiles of proteasome inhibitors will also be investigated. The discovery of selective immunoproteasome inhibitors will not only benefit the elucidation of the biological functions of various subunits, but also be helpful to determine the effects of selective inhibition on the therapeutic profiles of the inhibitors.