VLX1570

VLX1570 is a small molecule b-AP15 analog that fucttion as proteasome deubiquitinase inhibitor with IC50 of 10 uM, interacts at the active sites of the proteasome DUBs USP14 and UCHL5; demonstrates cytotoxicity in survival assays in HCT116 colon cancer cells with IC50 of 0.58 uM, shows no inhibitory activity on a panel of recombinant non-proteasome DUBs, recombinant kinases, or caspase-3; decreases cell viability in chemotherapy resistant endometrial cancer cells consistent with cell cycle arrest and caspase-3 mediated apoptosis; decreases tumor burden and prolongs survival in WM-xenografted mice.Blood Cancer Phase 2 Clinical (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. VLX1570 binds to recombinant USP14 with Kd of 1.5-18 μM using two different sources of recombinant protein, and the Kd 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-BZR 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. (In Vivo) :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.