Trader Darci J, Simanski Scott, Kodadek Thomas
Departments of Chemistry and Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
J Am Chem Soc. 2015 May 20;137(19):6312-9. doi: 10.1021/jacs.5b02069. Epub 2015 May 8.
The proteasome is a multisubunit complex responsible for most nonlysosomal 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 2013, 24, 791-805), suggesting that this subunit 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.
蛋白酶体是一种多亚基复合物，负责真核细胞中大多数非溶酶体途径的蛋白质周转。蛋白酶体抑制剂在临床上备受关注，尤其是用于治疗多发性骨髓瘤（MM）。不幸的是，几乎不可避免地会出现对这些靶向活性位点药物的耐药性。克服这种耐药性的一种策略是抑制蛋白酶体介导的蛋白质周转级联反应中的其他步骤。此前，安乔里等人将Rpn13鉴定为一种亲电化合物（RA-190）的靶点，该化合物对MM细胞具有选择性毒性（《癌细胞》，2013年，第24卷，第791 - 805页），这表明蛋白酶体的这个亚基也是一个可行的癌症药物靶点。在此，我们描述了首个高选择性、可逆性Rpn13配体的发现，并表明它们对MM细胞也具有选择性毒性。这些数据有力地支持了以下假设：Rpn13是开发治疗MM和其他癌症药物的一个可行靶点。
