Linked Life Data

19462975

Source:http://linkedlifedata.com/resource/pubmed/id/19462975

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
2009-7-2
pubmed:abstractText
The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1520-4804
pubmed:author
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
52
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3915-26
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc.
pubmed:affiliation
Chemical Genomics Centre of the Max Planck Society, D-44227 Dortmund, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't