Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02139, USA.
Drug Discov Today. 2010 Mar;15(5-6):243-9. doi: 10.1016/j.drudis.2010.01.008. Epub 2010 Jan 29.
Inhibition of the proteasome (a highly abundant enzymatic complex responsible for intracellular protein turnover) is an effective anti-cancer therapeutic approach, as demonstrated by the first-in-class agent bortezomib. Various new proteasome inhibitors are now in development, including peptide boronic acid analogs MLN9708 and CEP-18770, peptide epoxyketones carfilzomib and PR-047, and NPI-0052, a beta-lactone compound. All are potent inhibitors of proteasome activity in vitro but show differences in enzyme binding kinetics, which might affect their pharmacology and result in different efficacy and safety profiles. Here, we review the second-generation proteasome inhibitors and assess the potential pharmacologic impact of their different chemical properties.
蛋白酶体（一种高度丰富的酶复合物，负责细胞内蛋白质周转）的抑制是一种有效的抗癌治疗方法，这已被首个蛋白酶体抑制剂硼替佐米所证明。目前正在开发各种新型蛋白酶体抑制剂，包括肽硼酸类似物 MLN9708 和 CEP-18770、肽环氧酮 carfilzomib 和 PR-047 以及β-内酰胺化合物 NPI-0052。这些抑制剂在体外均能强烈抑制蛋白酶体活性，但在酶结合动力学方面存在差异，这可能影响其药理学特性，并导致不同的疗效和安全性特征。在这里，我们综述了第二代蛋白酶体抑制剂，并评估了它们不同化学性质对药理学的潜在影响。
