Linked Life Data

21216604

Source:http://linkedlifedata.com/resource/pubmed/id/21216604

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2011-3-1
pubmed:abstractText
Aberrant activation of oncogenic signal transducer and activator of transcription 3 (STAT3) protein signaling pathways has been extensively implicated in human cancers. Given STAT3's prominent dysregulatory role in malignant transformation and tumorigenesis, there has been a significant effort to discover STAT3-specific inhibitors as chemical probes for defining the aberrant STAT3-mediated molecular events that support the malignant phenotype. To identify novel, STAT3-selective inhibitors suitable for interrogating STAT3 signaling in tumor cells, we explored the design of hybrid molecules by conjugating a known STAT3 inhibitory peptidomimetic, ISS610 to the high-affinity STAT3-binding peptide motif derived from the ILR/gp-130. Several hybrid molecules were examined in in vitro biophysical and biochemical studies for inhibitory potency against STAT3. Lead inhibitor 14aa was shown to strongly bind to STAT3 (K(D)=900 nM), disrupt STAT3:phosphopeptide complexes (K(i)=5 ?M) and suppress STAT3 activity in in vitro DNA binding activity/electrophoretic mobility shift assay (EMSA). Moreover, lead STAT3 inhibitor 14aa induced a time-dependent inhibition of constitutive STAT3 activation in v-Src transformed mouse fibroblasts (NIH3T3/v-Src), with 80% suppression of constitutively-active STAT3 at 6h following treatment of NIH3T3/v-Src. However, STAT3 activity recovered at 24h after treatment of cells, suggesting potential degradation of the compound. Results further showed a suppression of aberrant STAT3 activity in NIH3T3/v-Src by the treatment with compound 14aa-OH, which is the non-pTyr version of compound 14aa. The effect of compounds 14aa and 14aa-OH are accompanied by a moderate loss of cell viability.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1464-3391
pubmed:author
pubmed:copyrightInfo
Copyright © 2010 Elsevier Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
19
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1823-38
pubmed:dateRevised
2011-8-9
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Design, synthesis, and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein.
pubmed:affiliation
Department of Chemistry, University of Toronto, Mississauga, ON, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural