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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2001-2-22
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pubmed:abstractText |
Src, a nonreceptor tyrosine kinase, is an important regulator of osteoclast-mediated resorption. We have investigated whether compounds that bind to the Src SH2 domain inhibit Src activity in cells and decrease osteoclast-mediated resorption. Compounds were examined for binding to the Src SH2 domain in vitro using a fluorescence polarization binding assay. Experiments were carried out with compounds demonstrating in vitro binding activity (nmol/L range) to determine if they inhibit Src SH2 binding and Src function in cells, demonstrate blockade of Src signaling, and lack cellular toxicity. Cell-based assays included: (1) a mammalian two-hybrid assay; (2) morphological reversion and growth inhibition of cSrcY527F-transformed cells; and (3) inhibition of cortactin phosphorylation in csk-/- cells. The Src SH2 binding compounds inhibit Src activity in all three of these mechanism-based assays. The compounds described were synthesized to contain nonhydrolyzable phosphotyrosine mimics that bind to bone. These compounds were further tested and found to inhibit rabbit osteoclast-mediated resorption of dentine. These results indicate that compounds that bind to the Src SH2 domain can inhibit Src activity in cells and inhibit osteoclast-mediated resorption.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
8756-3282
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pubmed:author |
pubmed-author:AdamsS ESE,
pubmed-author:AntoineEE,
pubmed-author:BardelayCC,
pubmed-author:BaronRR,
pubmed-author:BartlettCC,
pubmed-author:BohacekR SRS,
pubmed-author:DalgarnoD CDC,
pubmed-author:GuanWW,
pubmed-author:JacobsenV AVA,
pubmed-author:LesuisseDD,
pubmed-author:LynchB ABA,
pubmed-author:MacekK JKJ,
pubmed-author:MandineEE,
pubmed-author:RicklesR JRJ,
pubmed-author:SawyerT KTK,
pubmed-author:ShakespeareW CWC,
pubmed-author:SmithJ AJA,
pubmed-author:TakeuchiC SCS,
pubmed-author:VioletteS MSM,
pubmed-author:WeigeleMM,
pubmed-author:YangMM,
pubmed-author:van SchravendijkM RMR
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pubmed:issnType |
Print
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pubmed:volume |
28
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
54-64
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:11165943-Actins,
pubmed-meshheading:11165943-Amino Acid Sequence,
pubmed-meshheading:11165943-Animals,
pubmed-meshheading:11165943-Bone Resorption,
pubmed-meshheading:11165943-Cell Line, Transformed,
pubmed-meshheading:11165943-Dentin,
pubmed-meshheading:11165943-Diphosphonates,
pubmed-meshheading:11165943-Enzyme Inhibitors,
pubmed-meshheading:11165943-Fibroblasts,
pubmed-meshheading:11165943-Humans,
pubmed-meshheading:11165943-Ligands,
pubmed-meshheading:11165943-Mammals,
pubmed-meshheading:11165943-Mice,
pubmed-meshheading:11165943-Molecular Sequence Data,
pubmed-meshheading:11165943-Osteoclasts,
pubmed-meshheading:11165943-Osteoporosis,
pubmed-meshheading:11165943-Rabbits,
pubmed-meshheading:11165943-Radioligand Assay,
pubmed-meshheading:11165943-Rats,
pubmed-meshheading:11165943-Tritium,
pubmed-meshheading:11165943-Two-Hybrid System Techniques,
pubmed-meshheading:11165943-src Homology Domains,
pubmed-meshheading:11165943-src-Family Kinases
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pubmed:year |
2001
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pubmed:articleTitle |
Bone-targeted Src SH2 inhibitors block Src cellular activity and osteoclast-mediated resorption.
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pubmed:affiliation |
ARIAD Pharmaceuticals Inc., Cambridge, MA 02139, USA.
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pubmed:publicationType |
Journal Article
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