Wang Hui, Yang Qingzhu, Dou Q Ping, Yang Huanjie
School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China.
Department of Oncology and Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, MI, United States.
Curr Protein Pept Sci. 2018 Feb 13;19(4):358-367. doi: 10.2174/1389203718666170111121856.
Natural products serve as a main resource for drug discovery. The ubiquitin-proteasome system (UPS) is one of the primary intracellular protein degradation systems, which is responsible for the degradation of most short-lived, mis-folded and aged proteins. The proteasome is a validated target for cancer treatment, since cancer cells are more reliant on high levels of proteasome activity to maintain the dynamic protein homeostasis required for enhanced metabolism and unrestricted proliferation. Encouraged by success of bortezomib in the treatment of multiple myeloma, several second-generation proteasome inhibitors have been developed based on natural resources, and are being tested in various clinical settings. In this paper, we reviewed the most widely investigated proteasome inhibitors, including their natural product origins, compound-discovery and optimization, as well as their current status in both preclinical and clinical studies.
天然产物是药物发现的主要资源。泛素-蛋白酶体系统（UPS）是主要的细胞内蛋白质降解系统之一，负责降解大多数寿命较短、错误折叠和老化的蛋白质。蛋白酶体是已被验证的癌症治疗靶点，因为癌细胞更依赖高水平的蛋白酶体活性来维持增强代谢和无限制增殖所需的动态蛋白质稳态。受硼替佐米治疗多发性骨髓瘤成功的鼓舞，基于天然资源开发了几种第二代蛋白酶体抑制剂，并正在各种临床环境中进行测试。在本文中，我们综述了研究最广泛的蛋白酶体抑制剂，包括它们的天然产物来源、化合物发现与优化，以及它们在临床前和临床研究中的现状。
