Identification of 4-arylidene curcumin analogues as novel proteasome inhibitors for potential anticancer agents targeting 19S regulatory particle associated deubiquitinase
Identification of 4-arylidene curcumin analogues as novel proteasome inhibitors for potential anticancer agents targeting 19S regulatory particle associated deubiquitinase
复制标题
鉴定 4-亚芳基姜黄素类似物作为新型蛋白酶体抑制剂，用于靶向 19S 调节颗粒相关去泛素酶的潜在抗癌药物
DOI：
10.1016/j.bcp.2017.04.032
复制
发表时间：
2017-08-01
影响因子：
5.8
通讯作者：
Bu, Xianzhang
中科院分区：
文献类型：
--
作者：
Yue, Xin;Zuo, Yinglin;Bu, Xianzhang
蛋白酶体19 S调节颗粒（RP）相关的去泛素化酶（DUBS）由于其作为肿瘤治疗靶点的潜力而受到广泛关注。识别针对19 S RP相关DUBS的新实体并阐明潜在机制对于发现新型蛋白酶体阻断剂至关重要。在这项研究中，一系列4-亚芳基姜黄素类似物被确定为有效的蛋白酶体抑制剂，优先阻断蛋白酶体19 S RP的去泛素化酶功能，中度抑制20 S CP。最具活性的化合物33对19 S RP相关的泛素特异性蛋白酶14表现出主要的抑制作用，沿着对泛素C-末端水解酶5表现出较小的作用，这导致蛋白酶体功能障碍，随后在几种癌细胞中积累泛素化蛋白（如ha）。值得注意的是，尽管19 S RP和20 S CP抑制均诱导显著的内质网应激并触发半胱天冬酶-12/9通路活化以促进癌细胞凋亡，但33的19 S RP抑制避免了缓慢的起始时间、Bcl-2过表达和PERK-磷酸化，这有助于临床药物硼替佐米的不足。这些系统性研究为开发新型蛋白酶体抑制剂用于癌症治疗提供了见解。(C)2017爱思唯尔公司All rights reserved.
The proteasomal 19S regulatory particle (RP) associated deubiquitinases (DUBS) have attracted much attention owing to their potential as a therapeutic target for cancer therapy. Identification of new entities against 19S RP associated DUBS and illustration of the underlying mechanisms is crucial for discovery of novel proteasome blockers. In this study, a series of 4-arylidene curcumin analogues were identified as potent proteasome inhibitor by preferentially blocking deubiquitinase function of proteasomal 19S RP with moderate 20S CP inhibition. The most active compound 33 exhibited a major inhibitory effect on 19S RP-associated ubiquitin-specific proteases 14, along with a minor effect on ubiquitin C-terminal hydrolase 5, which resulted in dysfunction of proteasome, and subsequently accumulated ubiquitinated proteins (such as ha) in several cancer cells. Remarkably, though both 19S RP and 20S CP inhibition induced significantly endoplasmic reticulum stress and triggered caspase-12/9 pathway activation to promote cancer cell apoptosis, the 19S RP inhibition by 33 avoided slow onset time, Bcl-2 overexpression, and PERK-phosphorylation, which contribute to the deficiencies of clinical drug Bortezomib. These systematic studies provided insights in the development of novel proteasome inhibitors for cancer treatment. (C) 2017 Elsevier Inc. All rights reserved.