VLX1570

VLX1570 is a competitive inhibitor of proteasome deubiquitinases (DUBs) with an IC₅₀ of approximate 10 μM. IC50 & Target: IC50: appr 10?μM (Deubiquitinase)^[2] In Vitro: VLX1570 inhibits USP14 and UCHL5 activity of 19S regulatory particles, and the inhibition of USP14 is more pronounced. VLX1570 (1 μM) shows inhibitory activity against USP14 in KMS-11 myeloma cells. VLX1570 exhibits an IC₅₀ of 0.58 μM on HCT116 cells^[1]. VLX1570 binds to recombinant USP14 with K_d of 1.5-18?μM using two different sources of recombinant protein, and the K_d for recombinant UCHL5 is higher (14-18?μM) compared to that of USP14. VLX1570 has potent antiproliferative activities on multiple myeloma cells, with IC₅₀s of 43?±?2 nM, 74?±?2 nM, 126?±?3 nM, and 191?±?1 nM for KMS-11, RPMI8226, OPM-2, and OPM-2-BZ^R cells, respectively^[2]. VLX1570 suppresses the viability of BCWM.1 cells, with an EC₅₀ of 20.22?nM. VLX1570 (100, 250, 500 nM) induces significant apoptosis by 12?h in a dose-dependent manner in all Waldenstrom macroglobulinemia (WM) cell lines tested, including BCWM.1/IR (IR) and BCWM.1/BR (BR) subclones. VLX1570 (100, 250, 500 nM) also causes ER stress machinery and mitochondrial damage in WM cells. VLX1570 (250?nM) downregulates BCR-signalosome components and their end effectors, as well as CXCR4 expression in WM cells^[3]. In Vivo: VLX1570 (3?mg/kg) significantly decreases tumor growth in mice bearing KMS-11 multiple myeloma cells^[2]. VLX1570 (4.4?mg/kg, i.p.) markedly suppresses tumor growth, without obvious weight loss and other signs of systemic toxicity in the Waldenstrom macroglobulinemia (WM)-bearing mice^[3].