In:
Chemical Biology & Drug Design, Wiley, Vol. 86, No. 5 ( 2015-11), p. 1036-1048
Abstract:
The ubiquitin–proteasome system ( UPS ) is increasingly recognized as a therapeutic target for the development of anticancer 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‐ AP 15 as an inhibitor of 19S proteasome deubiquitinase ( DUB ) activity. Building upon our previous data, we performed a structure–activity relationship ( SAR ) study on b‐ AP 15 and identified VLX 1570 as an analog with promising properties, including enhanced potency and improved solubility in aqueous solution. In silico modeling was consistent with interaction of VLX 1570 with key cysteine residues located at the active sites of the proteasome DUB s USP 14 and UCHL 5. VLX 1570 was found to inhibit proteasome deubiquitinase activity in vitro in a manner consistent with competitive inhibition. Furthermore, using active‐site‐directed probes, VLX 1570 also inhibited proteasome DUB activity in exposed cells. Importantly, VLX 1570 did not show inhibitory activity on a panel of recombinant non‐proteasome DUB s, on recombinant kinases, or on caspase‐3 activity, suggesting that VLX 1570 is not an overtly reactive general enzyme inhibitor. Taken together, our data shows the chemical and biological properties of VLX 1570 as an optimized proteasome DUB inhibitor.
Type of Medium:
Online Resource
ISSN:
1747-0277
,
1747-0285
DOI:
10.1111/cbdd.2015.86.issue-5
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2216600-2
SSG:
12
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