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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
|
| pubmed:dateCreated |
1999-2-11
|
| pubmed:abstractText |
Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell membrane penetration. Work presented in the current study examines a variety of pTyr mimetics in the context of a high-affinity Grb2 binding platform. Among the analogues studied are new non-phosphorus-containing pTyr mimetics 23a and 23b which, when incorporated into tripeptide structures 18f and 20f, are able to inhibit Grb2 SH2 domain binding with affinities among the best yet reported for non-phosphorus-containing SH2 domain inhibitors (IC50 values of 6.7 and 1.3 microM, respectively). The present study has also demonstrated the usefulness of the Nalpha-oxalyl group as an auxiliary which enhances the binding potency of both phosphorus- and non-phosphorus-containing pTyr mimetics. When combined with the (phosphonomethyl)phenylalanine (Pmp) residue to give analogues such as L-20d, potent inhibition of Grb2 SH2 domain binding can be achieved both in extracellular assays using isolated Grb2 SH2 domain protein and in intracellular systems measuring the association of endogenous Grb2 with its cognate p185erbB-2 ligand. These latter effects can be achieved at micromolar to submicromolar concentrations without prodrug derivatization. The oxalyl-containing pTyr mimetics presented in this study should be of general usefulness for the development of other Grb2 SH2 domain antagonists, independent of the beta-bend-mimicking platform utilized for their display.
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| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/4-phosphonomethylphenylalanine,
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Asparagine,
http://linkedlifedata.com/resource/pubmed/chemical/GRB2 Adaptor Protein,
http://linkedlifedata.com/resource/pubmed/chemical/GRB2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Phenylalanine,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphonic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphotyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, erbB-2,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jan
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
14
|
| pubmed:volume |
42
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
25-35
|
| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:9888830-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:9888830-Asparagine,
pubmed-meshheading:9888830-Female,
pubmed-meshheading:9888830-GRB2 Adaptor Protein,
pubmed-meshheading:9888830-Humans,
pubmed-meshheading:9888830-Ligands,
pubmed-meshheading:9888830-Models, Molecular,
pubmed-meshheading:9888830-Molecular Mimicry,
pubmed-meshheading:9888830-Phenylalanine,
pubmed-meshheading:9888830-Phosphonic Acids,
pubmed-meshheading:9888830-Phosphotyrosine,
pubmed-meshheading:9888830-Protein Binding,
pubmed-meshheading:9888830-Proteins,
pubmed-meshheading:9888830-Receptor, erbB-2,
pubmed-meshheading:9888830-Recombinant Proteins,
pubmed-meshheading:9888830-Structure-Activity Relationship,
pubmed-meshheading:9888830-Surface Plasmon Resonance,
pubmed-meshheading:9888830-Tumor Cells, Cultured,
pubmed-meshheading:9888830-src Homology Domains
|
| pubmed:year |
1999
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| pubmed:articleTitle |
Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands.
|
| pubmed:affiliation |
Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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| pubmed:publicationType |
Journal Article
|