泛素-蛋白酶体及其抑制剂分类与合成.pdfVIP

药学学报 Acta Pharmaceutica Sinica 2009, 44 ( 12) : 1313 1319 ·1313 · ·综述· 泛素-蛋白酶体及其抑制剂的分类与合成 * 景, 张大永, 吴晓明 ( 中国 科大学 学院, 江苏 南京 210009) 摘要: 泛素-蛋白酶体是人体内降解蛋白质的主要途径, 通过该酶体来抑制蛋白质的降解是近年来治疗癌症 的新策略, 同时还扩大了化学治疗药的靶标。该蛋白酶体调控着人体内非必需或废弃细胞蛋白的降解, 这一过程 在许多癌症细胞中往往调控紊乱。基于这个靶标, 治疗多发性骨髓瘤的二肽硼酸类化合物 Bortezomib, 在 2003 年得到了FDA 的批准, 成为该靶点 一个成功上市的 物。随后一系列具有蛋白酶20S 抑制活性的合成小分子 化合物或提取的天然化合物进入临床实验。本文主要综述了蛋白酶体的结构、蛋白酶抑制剂的作用机制及其抑 制剂的合成与分类。 关键词: 蛋白质的降解; 泛素-蛋白酶系统 (UPP); 抑制剂; 抗肿瘤活性 中图分类号: R916 文献标识码:A 文章编号: 05 13-4870 (2009) 12-13 13-07 Classification and synthesis of ubiquitin-proteasome inhibitor * LI Jing, ZHANG Da-yong , WU Xiao-ming (School of Pharmacy, China Pharmaceutical University, Nanj ing 210009, China) Abstract: The inhibition of protein degradation through the ubiquitin-proteasome pathway is a recently developed approach to cancer treatment which extends the range of cellular target for chemotherapy. This therapeutic strategy is very interesting since the proteasomes carry out the regulated degradation of unnecessary or damaged cellular proteins, a process that is dysregulated in many cancer cells. Based on this hypothesis, the proteasome complex inhibitor Bortezomib was approved for use in multiple myeloma patients by FDA in 2003. Drug discovery programs in academy and the pharmaceutical industry have developed a range of synthetic and natural inhibitors of the 20S proteasome core particle that have entered human clinical trials as signi cant