VLX1570 is a deubiquitinylating enzymeDUB competitive inhibitor with an IC50 of approximately 10 μM in vitro and shows coinhibition of the deubiquitinating enzymes, like USP14 and UCHL5.
Deubiquitinating enzymes (DUBs) are key components of the ubiquitin-dependent protein degradation pathway and act as master regulators in a number of metabolic processes including cell growth, differentiation, and apoptosis[3]. VLX1570 is a competitive inhibitor of proteasome DUB activity with IC50 value of 10 μM. In vitro, VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Inhibition of USP14 activity could be demonstrated in cells exposed to 0.5 μM VLX1570 whereas UCHL5 inhibition was weak in comparison. VLX1570 inhibited multiple myeloma cells proliferation, including KMS-11, RPMI8226, OPM-2 and OPM-2-BZR cell lines, with IC50 values ranging in 43 – 191 nM[4]. In addition, VLX1570 inhibited cell viability of ALL cell lines including 697, Reh, SEM, RS4;11, SUP-B15, CCRF-CEM and T-ALL cell lines, with IC50 values ranging in 50 - 100 nM, suggesting its highly sensitive to acute lymphoblastic leukemia cells[5]. In vivo, administered VLX1570 at 4.0 mg/kg via intraperitoneal injection every alternate day for 20 days resulted in decreased tumor burden and prolonged survival in waldenstrom macroglobulinemia tumor xenografted mice[6]. Treatment of a xenograft mouse model of ewing sarcoma (EWS) with VLX1570 at dose of 4.4 mg/kg once daily via intraperitoneal administration for 2 weeks significantly inhibited in vivo tumor growth[7].
作用机制
VLX1570 interferes with the proteasomal degradation by inhibiting the activities of the proteasomal DUBs USP14 and UCHL5[5].
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