|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
2
|
|
pubmed:dateCreated |
2006-3-7
|
|
pubmed:abstractText |
Hsp90 encodes a ubiquitous molecular chaperone protein conserved among species which acts on multiple substrates, many of which are important cell-signaling proteins. Inhibition of Hsp90 function has been promoted as a mechanism to degrade client proteins involved in tumorigenesis and disease progression. Several assays to monitor inhibition of Hsp90 function currently exist but are limited in their use for a drug discovery campaign. Using data from the crystal structure of an initial hit compound, we have developed a fluorescence polarization assay to monitor binding of compounds to the ATP-binding site of Hsp90. This assay is very robust (Z' > 0.9) and can detect affinity of compounds with IC50s to 40 nM. We have used this assay in conjunction with cocrystal structures of small molecules to drive a structure-based design program aimed at the discovery and optimization of a novel class of potent Hsp90 inhibitors.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Mar
|
|
pubmed:issn |
0003-2697
|
|
pubmed:author |
pubmed-author:BarrilXX,
pubmed-author:CheungK-MKM,
pubmed-author:DrysdaleM JMJ,
pubmed-author:DymockB WBW,
pubmed-author:GrantKK,
pubmed-author:HowesRR,
pubmed-author:JamesKK,
pubmed-author:MatthewsTT,
pubmed-author:McDonaldEE,
pubmed-author:NorthfieldC JCJ,
pubmed-author:RobertsonA G SAG,
pubmed-author:SurgenorAA,
pubmed-author:WayneJJ,
pubmed-author:WorkmanPP,
pubmed-author:WrightLL
|
|
pubmed:issnType |
Print
|
|
pubmed:day |
15
|
|
pubmed:volume |
350
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
202-13
|
|
pubmed:dateRevised |
2006-11-15
|
|
pubmed:meshHeading |
pubmed-meshheading:16460658-Adenosine Triphosphatases,
pubmed-meshheading:16460658-Binding Sites,
pubmed-meshheading:16460658-Coumarins,
pubmed-meshheading:16460658-Crystallography, X-Ray,
pubmed-meshheading:16460658-Fluorescence Polarization,
pubmed-meshheading:16460658-HSP90 Heat-Shock Proteins,
pubmed-meshheading:16460658-Inhibitory Concentration 50,
pubmed-meshheading:16460658-Pyrazoles,
pubmed-meshheading:16460658-Resorcinols,
pubmed-meshheading:16460658-Saccharomyces cerevisiae,
pubmed-meshheading:16460658-Structure-Activity Relationship
|
|
pubmed:year |
2006
|
|
pubmed:articleTitle |
A fluorescence polarization assay for inhibitors of Hsp90.
|
|
pubmed:affiliation |
Vernalis (Cambridge), Granta Park, Great Abington, Cambridge CB1 6GB, UK. r.howes@vernalis.com
|
|
pubmed:publicationType |
Journal Article
|
