VLX1570 is a competitive inhibitor of proteasome deubiquitinases (DUBs) with an IC₅₀ of approximate 10 μM.

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. 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. 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.

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

VLX1570 (3 mg/kg) significantly decreases tumor growth in mice bearing KMS-11 multiple myeloma cells. 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.

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

VLX1570 (3 mg/kg) significantly decreases tumor growth in mice bearing KMS-11 multiple myeloma cells. 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.

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

• . Wang X, et al. Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15. Chem Biol Drug Des. 2015 Nov;86(5):1036-48.  [Content Brief]

  . Wang X, et al. The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Sci Rep. 2016 Jun 6;6:26979.  [Content Brief]

  . Paulus A, et al. Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells. Blood Cancer J. 2016 Nov 4;6(11):e492.  [Content Brief]