Linked Life Data

20472436

Source:http://linkedlifedata.com/resource/pubmed/id/20472436

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2010-6-23
pubmed:abstractText
The current paper presents the synthesis and evaluation of a series of maleimides that were designed to inhibit the Cdc25 phosphatase by alkylation of catalytically essential cysteine residues. Although in HepB3 cell culture assays the analogues did exhibit antiproliferative IC(50) values ranging from sub-micromolar to greater than 100 microM, inhibition of Cdc25 through cysteine alkylation could not be demonstrated. It was also found that analysis using fluorescence activated cell sorting (FACS) following treatment with the most potent analogue (1t) did not provide data consistent with inhibition at one specific point in the cell cycle, as would be expected if Cdc25A were inhibited. Further studies with a subset of analogues resulted in a correlation of antiproliferative potencies with activation of the unfolded protein response (UPR). The UPR is a regulatory pathway that temporarily suspends protein production when misfolding of proteins occurs within the endoplastic reticulum (ER). In addition, ER chaperones that promote proper refolding become up-regulated. If cellular damage cannot be resolved by these mechanisms, then the UPR can initiate apoptosis. The current study indicates that these maleimide analogues lead to UPR activation, which is predictive of the selective antiproliferative activity of the series.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-12324512, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-12461518, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-12813455, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-12871976, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-14635196, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-15775988, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-16432136, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-16488126, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-16818510, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-16930563, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-16953201, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-17565364, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-17979528, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-18038217, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-19131336, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-19190324, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-19360473, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-7499329, http://linkedlifedata.com/resource/pubmed/commentcorrection/20472436-9930704
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1464-3391
pubmed:author
pubmed:copyrightInfo
Published by Elsevier Ltd.
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
18
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4535-41
pubmed:dateRevised
2011-9-29
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Development of antiproliferative phenylmaleimides that activate the unfolded protein response.
pubmed:affiliation
Chemical Biology Laboratory, Molecular Discovery Program, NCI-Frederick, Frederick, MD 21702, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural