College of Pharmacy, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
Center for Advanced Biomolecular Recognition, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
Arch Pharm Res. 2023 Jul;46(7):573-597. doi: 10.1007/s12272-023-01455-0. Epub 2023 Aug 5.
As the ubiquitin-proteasome system (UPS) regulates almost every biological process, the dysregulation or aberrant expression of the UPS components causes many pathological disorders, including cancers. To find a novel target for anticancer therapy, the UPS has been an active area of research since the FDA's first approval of a proteasome inhibitor bortezomib in 2003 for treating multiple myeloma (MM). Here, we summarize newly described UPS components, including E3 ubiquitin ligases, deubiquitinases (DUBs), and immunoproteasome, whose malfunction leads to tumorigenesis and whose inhibitors have been investigated in clinical trials as anticancer therapy since 2020. We explain the mechanism and effects of several inhibitors in depth to better comprehend the advantages of targeting UPS components for cancer treatment. In addition, we describe attempts to overcome resistance and limited efficacy of some launched proteasome inhibitors, as well as an emerging PROTAC-based tool targeting UPS components for anticancer therapy.
由于泛素-蛋白酶体系统 (UPS) 调节着几乎所有的生物过程，因此 UPS 组件的失调或异常表达会导致许多病理紊乱，包括癌症。为了寻找抗癌治疗的新靶点，自 2003 年 FDA 首次批准蛋白酶体抑制剂硼替佐米用于治疗多发性骨髓瘤 (MM) 以来，UPS 一直是研究的热点领域。在这里，我们总结了新描述的 UPS 组件，包括 E3 泛素连接酶、去泛素化酶 (DUBs) 和免疫蛋白酶体，它们的功能障碍导致肿瘤发生，自 2020 年以来，其抑制剂已在临床试验中作为抗癌疗法进行了研究。我们深入解释了几种抑制剂的作用机制和效果，以更好地理解针对 UPS 组件进行癌症治疗的优势。此外，我们还描述了克服一些已上市的蛋白酶体抑制剂的耐药性和有限疗效的尝试，以及一种新兴的基于 PROTAC 的针对 UPS 组件的抗癌治疗工具。
