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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
22
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pubmed:dateCreated |
1998-11-23
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pubmed:abstractText |
Phosphorylated tyrosine residues of growth factor receptors that associate with intracellular proteins containing src-homology 2 (SH2) domains are integral components in several signal transduction pathways related to proliferative diseases such as cancer, atherosclerosis, and restenosis. In particular, a phosphorylated pentapeptide [pTyr751-Val-Pro-Met754-Leu (pTyr = phosphotyrosine)] derived from the primary sequence of platelet-derived growth factor-beta (PDGF-beta) receptor blocks the association of the C-terminal SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) to PDGF-beta receptor with an IC50 of 0.445 +/- 0.047 microM. Further evaluation of the structure-activity relationships for pTyr751-Val-Pro-Met-Leu resulted in the design of smaller peptidomimetics with enhanced affinity including Ac-pTyr-Val-Ala-N(C6H13)2 (IC50 = 0.076 +/- 0.010 microM). In addition, the phosphotyrosine residue was replaced with a difluorophosphonate derivative [4-phosphono(difluoromethyl)phenylalanine (CF2Pmp)] which has been shown to be stable to cellular phosphatases. The extracellular administration of either CF2Pmp-Val-Pro-Met-Leu or Ac-CF2Pmp-Val-Pro-Met-NH2 in a whole cell assay resulted in specific inhibition of the PDGF-stimulated association from the C-terminal SH2 domain of the p85 subunit of PI 3-kinase to the PDGF-beta receptor in a dose-dependent manner. These compounds were also effective in inhibiting GLUT4 translocation, c-fos expression, and cell membrane ruffling in single-cell microinjection assay.
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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 |
http://linkedlifedata.com/resource/pubmed/chemical/Glucose Transporter Type 4,
http://linkedlifedata.com/resource/pubmed/chemical/Monosaccharide Transport Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Muscle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoric Monoester Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-fos,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Platelet-Derived Growth...,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Platelet-Derived Growth...,
http://linkedlifedata.com/resource/pubmed/chemical/Slc2a4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Slc2a4 protein, rat
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
22
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pubmed:volume |
41
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4329-42
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:9784108-3T3 Cells,
pubmed-meshheading:9784108-Animals,
pubmed-meshheading:9784108-Cell Cycle,
pubmed-meshheading:9784108-Cell Membrane Permeability,
pubmed-meshheading:9784108-Glucose Transporter Type 4,
pubmed-meshheading:9784108-Mice,
pubmed-meshheading:9784108-Microinjections,
pubmed-meshheading:9784108-Microscopy, Fluorescence,
pubmed-meshheading:9784108-Models, Molecular,
pubmed-meshheading:9784108-Molecular Mimicry,
pubmed-meshheading:9784108-Monosaccharide Transport Proteins,
pubmed-meshheading:9784108-Muscle, Smooth, Vascular,
pubmed-meshheading:9784108-Muscle Proteins,
pubmed-meshheading:9784108-Oligopeptides,
pubmed-meshheading:9784108-Peptides,
pubmed-meshheading:9784108-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:9784108-Phosphoric Monoester Hydrolases,
pubmed-meshheading:9784108-Proto-Oncogene Proteins c-fos,
pubmed-meshheading:9784108-Rats,
pubmed-meshheading:9784108-Receptor, Platelet-Derived Growth Factor beta,
pubmed-meshheading:9784108-Receptors, Platelet-Derived Growth Factor,
pubmed-meshheading:9784108-Structure-Activity Relationship,
pubmed-meshheading:9784108-src Homology Domains
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pubmed:year |
1998
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pubmed:articleTitle |
Design of peptidomimetics that inhibit the association of phosphatidylinositol 3-kinase with platelet-derived growth factor-beta receptor and possess cellular activity.
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pubmed:affiliation |
Departments of Chemistry and Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
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pubmed:publicationType |
Journal Article
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