Repurposing old drugs as new inhibitors of the ubiquitin-proteasome pathway for cancer treatment

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
出处
期刊:Seminars in Cancer Biology [Elsevier]
卷期号:68: 105-122 被引量:26
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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