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].
VLX1570 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Primary WM tumor cells
250 nM
12 h
To evaluate the apoptosis-inducing effect of VLX1570 on primary WM cells, results showed that VLX1570 induced apoptosis and PARP-1 cleavage at 250 nM.
Blood Cancer J. 2016 Nov 4;6(11):e492.
BCWM.1/BR cells
29 nM
72 h
To evaluate the cytotoxicity of VLX1570 on BCWM.1/BR cells, results showed that VLX1570 effectively inhibited cell viability at 29 nM.
Blood Cancer J. 2016 Nov 4;6(11):e492.
WM cell lines and drug-resistant subclones
20 nM
72 h
To assess the sensitivity of WM cells to VLX1570, results showed that all WM cells were sensitive to VLX1570, with BCWM.1 cells being the most sensitive, showing 50% loss of viability at 20 nM VLX1570.
Blood Cancer J. 2016 Nov 4;6(11):e492.
LNCaP cells
5 μM
15 min
VLX1570 markedly increased the overall levels of high-molecular weight ubiquitylated proteins but did not result in AR ubiquitylation, indicating that the high molecular weight AR species generated by VLX1570 were not due to polyubiquitylation
Commun Biol. 2024 Jan 5;7(1):25.
VCaP cells
2.5 or 5.0 μM
4 h
VLX1570 significantly decreased AR in DHT-treated VCaP cells and increased high molecular weight AR, indicating a more pronounced effect of VLX1570 on AR in the presence of DHT
Commun Biol. 2024 Jan 5;7(1):25.
C4-2 cells
2.5 or 5.0 μM
4 h
VLX1570 significantly decreased AR in DHT-treated cells and increased high molecular weight AR, indicating a more pronounced effect of VLX1570 on AR in the presence of DHT
Commun Biol. 2024 Jan 5;7(1):25.
H1299 cells
1.25, 2.5, 5, 10, 25, 50, 100, 200, 400 nM
72 h
Evaluate the effect of VLX1570 on the viability of H1299 cells, results showed that VLX1570 significantly inhibited cell proliferation
J Cell Mol Med. 2022 Jan;26(1):108-122.
H460 cells
1.25, 2.5, 5, 10, 25, 50, 100, 200, 400 nM
72 h
Evaluate the effect of VLX1570 on the viability of H460 cells, results showed that VLX1570 significantly inhibited cell proliferation
J Cell Mol Med. 2022 Jan;26(1):108-122.
A549 cells
1.25, 2.5, 5, 10, 25, 50, 100, 200, 400 nM
72 h
Evaluate the effect of VLX1570 on the viability of A549 cells, results showed that VLX1570 significantly inhibited cell proliferation
J Cell Mol Med. 2022 Jan;26(1):108-122.
U2OS cells
5 μM and 20 μM
1 hour
To identify covalent targets of VLX1570 through chemical proteomics, results showed multiple covalent targets were identified, with CIAPIN1 being the most significant
J Med Chem. 2020 Apr 9;63(7):3756-3762.
Kasumi-1 cells
260 nM
Kasumi-1 cells showed moderate sensitivity to VLX1570 with an IC50 of 260 nM.
Biomolecules. 2021 Sep 10;11(9):1339.
HNT34 cells
273 nM
HNT34 cells showed moderate sensitivity to VLX1570 with an IC50 of 273 nM.
Biomolecules. 2021 Sep 10;11(9):1339.
KG1a cells
307 nM
KG1a cells showed lower sensitivity to VLX1570 with an IC50 of 307 nM.
Biomolecules. 2021 Sep 10;11(9):1339.
MOLM-14 cells
204 nM
MOLM-14 cells showed higher sensitivity to VLX1570 with an IC50 of 204 nM.
Biomolecules. 2021 Sep 10;11(9):1339.
HL-60
50 nM
3 h
VLX1570 induced the genetic pathway involved in “heat shock transcription factor 1 (HSF1) activation”, “HSF1 dependent transactivation”, and “Regulation of HSF1 mediated heat shock response”.
Cancer Sci. 2021 Aug;112(8):3302-3313.
VLX1570 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
A673 and TC-71 xenograft models
Intraperitoneal injection
4.4 mg/kg
Daily, continuous treatment
Evaluate the inhibitory effect of VLX1570 on tumor growth, results showed that VLX1570 significantly inhibited tumor growth
Cancer Res. 2016 Aug 1;76(15):4525-34
Mice
WM xenograft model
Intraperitoneal injection
4.4 mg/kg
Every alternate day for 21 days
To evaluate the anti-tumor activity of VLX1570 in WM xenograft mice, results showed that VLX1570 significantly reduced tumor volume and growth, and prolonged survival.
Blood Cancer J. 2016 Nov 4;6(11):e492.
Zebrafish
Zebrafish embryo model
Added to water
1 µM
72 hours
VLX1570 significantly inhibited the growth and spread of KG1a and MOLM-14 cells.
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