Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA; email:
Annu Rev Pharmacol Toxicol. 2020 Jan 6;60:457-476. doi: 10.1146/annurev-pharmtox-010919-023603. Epub 2019 Sep 3.
Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.
蛋白酶体是一种大型的、多催化的蛋白质复合物，能够将细胞内的蛋白质切割成肽段。有许多不同形式的蛋白酶体，它们在催化活性亚基、调节亚基和相关蛋白方面存在差异。蛋白酶体抑制剂是治疗多发性骨髓瘤和套细胞淋巴瘤的一类重要药物，它们也正在被研究用于治疗其他疾病。硼替佐米（万珂）是第一个获得美国食品和药物管理局批准的蛋白酶体抑制剂。卡非佐米（凯洛斯）和伊沙佐米（恩莱瑞）最近也获得了批准，还有更多的药物正在开发中。虽然主要的作用机制是抑制蛋白酶体，但导致选择性细胞死亡的下游事件并不完全清楚。蛋白酶体抑制剂已被发现会影响蛋白质周转，但在浓度上远高于临床应用的浓度，这使得一些蛋白酶体抑制剂的作用可能是通过其他机制介导的。
