A reversible and highly selective inhibitor of the proteasomal ubiquitin receptor rpn13 is toxic to multiple myeloma cells.
A reversible and highly selective inhibitor of the proteasomal ubiquitin receptor rpn13 is toxic to multiple myeloma cells.
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DOI：
10.1021/jacs.5b02069
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发表时间：
2015-05-20
影响因子：
15
通讯作者：
Kodadek T
中科院分区：
文献类型：
--
作者：
Trader DJ;Simanski S;Kodadek T
蛋白酶体是一种多亚基复合物，负责真核细胞中蛋白质的大多数非溶酶体周转。蛋白酶体抑制剂在临床上，特别是在治疗多发性骨髓瘤（MM）方面具有很大的意义。不幸的是，对这些活性位点靶向药物的耐药性几乎不可避免地出现。克服这种抗性的一种策略是抑制由蛋白酶体介导的蛋白质周转级联中的其他步骤。先前，Anchoori等人鉴定Rpn 13为亲电子化合物（RA-190）的靶标，所述亲电子化合物对MM细胞具有选择性毒性（Cancer Cell 24，791-805（2013）），表明蛋白酶体的该亚基也是可行的癌症药物靶标。在这里，我们描述了第一个高选择性，可逆的Rpn 13配体的发现，并表明，他们也选择性毒性MM细胞。这些数据强烈支持Rpn 13是开发治疗MM和其他癌症的药物的可行靶标的假设。
The proteasome is a multi-subunit complex responsible for most non-lysosomal turnover of proteins in eukaryotic cells. Proteasome inhibitors are of great interest clinically, particularly for the treatment of multiple myeloma (MM). Unfortunately, resistance arises almost inevitably to these active site-targeted drugs. One strategy to overcome this resistance is to inhibit other steps in the protein turnover cascade mediated by the proteasome. Previously, Anchoori et al. identified Rpn13 as the target of an electrophilic compound (RA-190) that was selectively toxic to MM cells (Cancer Cell 24, 791–805 (2013)), suggesting that this sub-unit of the proteasome is also a viable cancer drug target. Here we describe the discovery of the first highly selective, reversible Rpn13 ligands and show that they are also selectively toxic to MM cells. These data strongly support the hypothesis that Rpn13 is a viable target for the development of drugs to treat MM and other cancers.
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影响因子：
50.3
作者：
Anchoori RK;Karanam B;Peng S;Wang JW;Jiang R;Tanno T;Orlowski RZ;Matsui W;Zhao M;Rudek MA;Hung CF;Chen X;Walters KJ;Roden RB
通讯作者：
Roden RB
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.7
作者：
Harshbarger, Wayne;Miller, Chase;Sacchettini, James
通讯作者：
Sacchettini, James
影响因子：
64.8
作者：
Groll, M;Ditzel, L;Huber, R
通讯作者：
Huber, R
影响因子：
3.7
作者：
Al-Shami A;Jhaver KG;Vogel P;Wilkins C;Humphries J;Davis JJ;Xu N;Potter DG;Gerhardt B;Mullinax R;Shirley CR;Anderson SJ;Oravecz T
通讯作者：
Oravecz T