VLX1570 is an inhibitor of 19S proteasomal deubiquitinases with IC50 values of 6.4 and 13 μM for deubiquitinase activity in vitro using Ub-rhodamine and Ub-AMC, respectively, as substrates. It is selective for proteasomal deubiquitinases over a panel of deubiquitinases at 20 μM, but inhibits USP5 by greater than 50%, and over a panel of 211 kinases at 10 μM, but inhibits Cdk4 by 77%. VLX1570 binds to and inhibits recombinant ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5) in vitro, and inhibits the USP14 and UCHL5 activity of purified 19S proteasomes when used at a concentration of 50 μM. It inhibits the proliferation of KMS-11, RPMI-8226, OPM-2, and OPM-2-BZR multiple myeloma cells (IC50s = 43, 74, 126, and 191 nM, respectively), as well as induces apoptosis and increases the accumulation of polyubiquitinated proteins. VLX1570 (3 mg/kg per day for 10 days) increases survival and reduces tumor growth in KMS-11-LUC2 and RPMI-8226 mouse xenograft models, respectively.
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VLX1570 is a proteasome deubiquitinase inhibitor. It also exhibits antineoplastic activities.
