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The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

Overview of attention for article published in Scientific Reports, June 2016
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Title
The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells
Published in
Scientific Reports, June 2016
DOI 10.1038/srep26979
Pubmed ID
Authors

Xin Wang, Magdalena Mazurkiewicz, Ellin-Kristina Hillert, Maria Hägg Olofsson, Stefan Pierrou, Per Hillertz, Joachim Gullbo, Karthik Selvaraju, Aneel Paulus, Sharoon Akhtar, Felicitas Bossler, Asher Chanan Khan, Stig Linder, Padraig D’Arcy

Abstract

Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 is an inhibitor of proteasome DUB activity currently in clinical trials for relapsed multiple myeloma. Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations. Transient knockdown of USP14 or UCHL5 expression by electroporation of siRNA reduced the viability of multiple myeloma cells. Treatment of multiple myeloma cells with VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Sensitivity to VLX1570 was moderately affected by altered drug uptake, but was unaffected by overexpression of BCL2-family proteins or inhibitors of caspase activity. Finally, treatment with VLX1570 was found to lead to extended survival in xenograft models of multiple myeloma. Our findings demonstrate promising antiproliferative activity of VLX1570 in multiple myeloma, primarily associated with inhibition of USP14 activity.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 29 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 29 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 9 31%
Student > Bachelor 6 21%
Student > Ph. D. Student 5 17%
Student > Master 4 14%
Professor 2 7%
Other 3 10%
Readers by discipline Count As %
Agricultural and Biological Sciences 10 34%
Biochemistry, Genetics and Molecular Biology 6 21%
Chemistry 4 14%
Medicine and Dentistry 4 14%
Pharmacology, Toxicology and Pharmaceutical Science 2 7%
Other 3 10%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 22 August 2016.
All research outputs
#6,267,890
of 8,261,086 outputs
Outputs from Scientific Reports
#25,649
of 35,407 outputs
Outputs of similar age
#180,648
of 253,949 outputs
Outputs of similar age from Scientific Reports
#2,373
of 3,282 outputs
Altmetric has tracked 8,261,086 research outputs across all sources so far. This one is in the 13th percentile – i.e., 13% of other outputs scored the same or lower than it.
So far Altmetric has tracked 35,407 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 14.8. This one is in the 16th percentile – i.e., 16% of its peers scored the same or lower than it.
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We're also able to compare this research output to 3,282 others from the same source and published within six weeks on either side of this one. This one is in the 15th percentile – i.e., 15% of its contemporaries scored the same or lower than it.