Linked Life Data

14971902

Source:http://linkedlifedata.com/resource/pubmed/id/14971902

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2004-2-19
pubmed:abstractText
To develop potential antitumor agents directed toward HER2/ErbB2 overexpression in cancer, we have designed inhibitors of the recognition between the phosphotyrosine of the receptor and the SH2 domain of the adaptor protein Grb2. In the first part of the paper, we report the synthesis of mimetics of the constrained (alpha-Me)phosphotyrosine residue such as (alpha-Me)-4-phosphonomethylphenylalanine (-CH2PO3H2), (alpha-Me) 4-phosphonodifluoromethylphenylalanine (-CF2PO3H2), and (alpha-Me)-4-phosphonophenylalanine (-PO3H2). The incorporation of these residues in the mAZ-pTyr-Xaa-Asn-NH2 series provided compounds with very high affinity for the Grb2 SH2 domain, in the 10(-8)-10(-9) range of Kd values. These compounds behave as potent antagonists of the Grb2-Shc interaction. Our results highlight the importance of the doubly negative charge borne by the pY + 1 amino acid in accordance with the interactions observed in the complex crystallized between mAZ-pTyr-(alphaMe)pTyr-Asn-NH2 and the Grb2 SH2 domain. mAZ-pTyr-(alphaMe)pTyr-Asn-NH2 was derivatized as the S-acetyl thioester (SATE) of the phosphotyrosine residues, and its surrogates provided prodrugs with very potent antiproliferative activity on cells overexpressing HER2/ErbB2, with ED50 values amounting to 0.1 microM. Finally a new prodrug is put forth under the form of a monobenzyl ester of phosphate group that is as active as and much easier to synthesize than SATE prodrugs. These compounds show promising activity for further testing on in vivo models.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
26
pubmed:volume
47
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1223-33
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:14971902-Adaptor Proteins, Signal Transducing, pubmed-meshheading:14971902-Animals, pubmed-meshheading:14971902-Antineoplastic Agents, pubmed-meshheading:14971902-Binding, Competitive, pubmed-meshheading:14971902-Cell Line, Tumor, pubmed-meshheading:14971902-Cell Transformation, Neoplastic, pubmed-meshheading:14971902-Esters, pubmed-meshheading:14971902-GRB2 Adaptor Protein, pubmed-meshheading:14971902-Humans, pubmed-meshheading:14971902-Mice, pubmed-meshheading:14971902-Molecular Mimicry, pubmed-meshheading:14971902-NIH 3T3 Cells, pubmed-meshheading:14971902-Phosphopeptides, pubmed-meshheading:14971902-Phosphotyrosine, pubmed-meshheading:14971902-Prodrugs, pubmed-meshheading:14971902-Proteins, pubmed-meshheading:14971902-Receptor, erbB-2, pubmed-meshheading:14971902-Structure-Activity Relationship, pubmed-meshheading:14971902-src Homology Domains
pubmed:year
2004
pubmed:articleTitle
Structure-activity relationships of small phosphopeptides, inhibitors of Grb2 SH2 domain, and their prodrugs.
pubmed:affiliation
Département de Pharmacochimie Moléculaire & Structurale, INSERM U266, CNRS FRE 2463, UFR des Sciences Pharmaceutiques et Biologiques, 4, Avenue de l'Observatoire, 75270 Paris 06, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't