泛素-蛋白酶体及其抑制剂的分类与合成

Classification and synthesis of ubiquitin-proteasome inhibitor

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,成为该靶点第一个成功上市的药物。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。

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 significant anti-cancer leads. The main results from the use of proteasome inhibition in cancer chemotherapy, the structure of several proteasome inhibitors and their synthesis is going to be reviewed in this paper.