Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/78401
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | New 26S proteasome inhibitors with high selectivity for chymotrypsin-like activity and p53-dependent cytotoxicity |
Author: | Neilsen, P. Pehere, A. Pishas, K. Callen, D. Abell, A. |
Citation: | ACS Chemical Biology, 2013; 8(2):353-359 |
Publisher: | American Chemical Society |
Issue Date: | 2013 |
ISSN: | 1554-8929 1554-8937 |
Statement of Responsibility: | Paul M. Neilsen, Ashok D. Pehere, Kathleen I. Pishas, David F. Callen, and Andrew D. Abell |
Abstract: | The 26S proteasome has emerged over the past decade as an attractive therapeutic target in the treatment of cancers. Here, we report new tripeptide aldehydes that are highly specific for the chymotrypsin-like catalytic activity of the proteasome. These new specific proteasome inhibitors demonstrated high potency and specificity for sarcoma cells, with therapeutic windows superior to those observed for benchmark proteasome inhibitors, MG132 and Bortezomib. Constraining the peptide backbone into the β-strand geometry, known to favor binding to a protease, resulted in decreased activity in vitro and reduced anticancer activity. Using these new proteasome inhibitors, we show that the presence of an intact p53 pathway significantly enhances cytotoxic activity, thus suggesting that this tumor suppressor is a critical downstream mediator of cell death following proteasomal inhibition. |
Keywords: | Tumor Cells, Cultured Humans Proteasome Endopeptidase Complex Chymotrypsin Leupeptins Cell Death Cell Survival Molecular Structure Structure-Activity Relationship Dose-Response Relationship, Drug Tumor Suppressor Protein p53 Proteasome Inhibitors |
Rights: | © 2012 American Chemical Society |
DOI: | 10.1021/cb300549d |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1009452 |
Published version: | http://dx.doi.org/10.1021/cb300549d |
Appears in Collections: | Aurora harvest IPAS publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.