VLX1570

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.^1,2 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%.¹ 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.^1,2 It inhibits the proliferation of KMS-11, RPMI-8226, OPM-2, and OPM-2-BZ^R multiple myeloma cells (IC₅₀s = 43, 74, 126, and 191 nM, respectively), as well as induces apoptosis and increases the accumulation of polyubiquitinated proteins.² 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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1. Wang, X., D'Arcy, P., Caulfield, T.R., et al. Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15. Chem. Biol. Drug Des. 86(5), 1036-1048 (2015).

2. Wang, X., Mazurkiewicz, M., Hillert, E.-K., et al. The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Sci. Rep. 6:26979, (2016).

Cho, C.-C., Li, S.G., Lalonde, T.J., et al. Drug repurposing for the SARS-CoV-2 papain-like protease. ChemMedChem 17(1), e202100455 (2022).