Linked Life Data

18680272

Source:http://linkedlifedata.com/resource/pubmed/id/18680272

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
16
pubmed:dateCreated
2008-8-25
pubmed:abstractText
Kinases are important targets in molecular cancer therapy. However, the evolutionary relatedness and structural conservation of these proteins often lead to unforeseen cross reactivity, yielding unexpected side effects. Thus, the use of promiscuous drugs is likely to introduce dangerous clinical uncertainties. Here, we show how to rationally redesign two promiscuous kinase inhibitors, staurosporine (7) and EKB-569 (8), with the goal of turning them into more selective ligands. This problem is addressed by exploiting a structure-based selectivity filter for specificity: the pattern of packing defects in the target. These singularities, called dehydrons, are solvent-exposed intramolecular hydrogen bonds that may be protected by drugs upon association and are not conserved across protein families. Our redesigned compounds possess a significantly focused activity, as experimentally corroborated in high-throughput screening assays. Thus, our design strategy proves to be operative to reduce the inhibitory impact of promiscuous kinase ligands, enhancing their safety as therapeutic agents.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1520-4804
pubmed:author
pubmed:issnType
Electronic
pubmed:day
28
pubmed:volume
51
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4890-8
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Redesigning kinase inhibitors to enhance specificity.
pubmed:affiliation
Department of Bioengineering, Rice University, Houston, Texas 77005, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural