A reversible and highly selective inhibitor of the proteasomal ubiquitin receptor rpn13 is toxic to multiple myeloma cells.
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.
Departments of Chemistry and Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
Darci J
DJ
Trader
Departments of Chemistry and Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
Scott
S
Simanski
Departments of Chemistry and Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
Thomas
T
Kodadek
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D034444:Peptoids / Q000737:chemistry* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism*
D000970:Antineoplastic Agents; D034444:Peptoids; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13