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Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b‐AP15

Overview of attention for article published in Chemical Biology & Drug Design, April 2015
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Title
Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b‐AP15
Published in
Chemical Biology & Drug Design, April 2015
DOI 10.1111/cbdd.12571
Pubmed ID
Authors

Wang, Xin, D'Arcy, Pádraig, Caulfield, Thomas R, Paulus, Aneel, Chitta, Kasyapa, Mohanty, Chitralekha, Gullbo, Joachim, Chanan‐Khan, Asher, Linder, Stig, Caulfield, Thomas R.

Abstract

The ubiquitin-proteasome system (UPS) is increasingly recognized as a therapeutic target for the development of anti-cancer therapies. The success of the 20S proteasome core particle (20S CP) inhibitor bortezomib in the clinical management of multiple myeloma has raised the possibility of identifying other UPS components for therapeutic intervention. We previously identified the small molecule b-AP15 as an inhibitor of 19S proteasome deubiquitinase (DUB) activity. Building upon our previous data we performed a structural activity relationship (SAR) study on b-AP15 and identified VLX1570 as an analog with promising properties, including enhanced potency and improved solubility in aqueous solution. In silico modeling was consistent with interaction of VLX1570 with key cysteine residues located at the active sites of the proteasome DUBs USP14 and UCHL5. VLX1570 was found to inhibit proteasomal deubiquitinase activity in vitro in a manner consistent with competitive inhibition. Furthermore using active site directed probes, VLX1570 also inhibited proteasome DUB activity in exposed cells. Importantly VLX1570 did not show inhibitory activity on a panel of recombinant non-proteasomal DUBs, on recombinant kinases or on caspase-3 activity, suggesting that VLX1570 is not an overtly reactive general enzyme inhibitor. Taken together our data shows the chemical and biological properties of VLX1570 as an optimized proteasome DUB inhibitor. This article is protected by copyright. All rights reserved.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 28 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 28 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 8 29%
Student > Bachelor 5 18%
Student > Ph. D. Student 5 18%
Student > Master 3 11%
Professor > Associate Professor 2 7%
Other 5 18%
Readers by discipline Count As %
Agricultural and Biological Sciences 7 25%
Chemistry 7 25%
Biochemistry, Genetics and Molecular Biology 6 21%
Unspecified 3 11%
Pharmacology, Toxicology and Pharmaceutical Science 1 4%
Other 4 14%

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 10 April 2015.
All research outputs
#4,703,328
of 6,362,439 outputs
Outputs from Chemical Biology & Drug Design
#314
of 694 outputs
Outputs of similar age
#115,559
of 161,868 outputs
Outputs of similar age from Chemical Biology & Drug Design
#8
of 12 outputs
Altmetric has tracked 6,362,439 research outputs across all sources so far. This one is in the 14th percentile – i.e., 14% of other outputs scored the same or lower than it.
So far Altmetric has tracked 694 research outputs from this source. They receive a mean Attention Score of 1.7. This one is in the 10th percentile – i.e., 10% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 161,868 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 17th percentile – i.e., 17% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 12 others from the same source and published within six weeks on either side of this one. This one is in the 25th percentile – i.e., 25% of its contemporaries scored the same or lower than it.