Carfilzomib公司
硼替佐米
蛋白酶体
药物重新定位
泛素
药物发现
药理学
药品
泛素连接酶
蛋白酶体抑制剂
癌症研究
蛋白质降解
多发性骨髓瘤
脱氮酶
医学
生物
生物信息学
免疫学
生物化学
基因
作者
Huanjie Yang,Xin Chen,Kai Li,Hassan Ali Cheaito,Qianqian Yang,Guojun Wu,Jinbao Liu,Q. Ping Dou
标识
DOI:10.1016/j.semcancer.2019.12.013
摘要
The ubiquitin-proteasome system (UPS) plays a central role in the degradation of cellular proteins. Targeting protein degradation has been validated as an effective strategy for cancer therapy since 2003. Several components of the UPS have been validated as potential anticancer targets, including 20S proteasomes, 19S proteasome-associated deubiquitinases (DUBs) and ubiquitin ligases (E3s). 20S proteasome inhibitors (such as bortezomib/BTZ and carfilzomib/CFZ) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM) and some other liquid tumors. Although survival of MM patients has been improved by the introduction of BTZ-based therapies, these clinical 20S proteasome inhibitors have several limitations, including emergence of resistance in MM patients, neuro-toxicities, and little efficacy in solid tumors. One of strategies to improve the current status of cancer treatment is to repurpose old drugs with UPS-inhibitory properties as new anticancer agents. Old drug reposition represents an attractive drug discovery approach compared to the traditional de novo drug discovery process which is time-consuming and costly. In this review, we summarize status of repurposed inhibitors of various UPS components, including 20S proteasomes, 19S-associated DUBs, and ubiquitin ligase E3s. The original and new mechanisms of action, molecular targets, and potential anticancer activities of these repurposed UPS inhibitors are reviewed, and their new uses including combinational therapies for cancer treatment are discussed.
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