Linked Life Data

16509576

Source:http://linkedlifedata.com/resource/pubmed/id/16509576

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2006-3-2
pubmed:abstractText
The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. An impressive number of synthetic Grb2-SH2 domain inhibitors have been identified; however, clinical agents operating by this mechanism are lacking, due in part to the unique requirement of anionic phosphate-mimicking functionality for high SH2 domain-binding affinity or the extended peptide nature of most inhibitors. In the current study, a new binding motif was successfully developed by the incorporation of 3'-substituted tyrosine derivatives into a simplified nonphosphorylated cyclic pentapeptide scaffold (4), which resulted in high affinity Grb2-SH2 inhibitors without any phosphotyrosine or phosphotyrosine mimetics. The new L-amino acid analogues bearing an additional nitro, amino, hydroxy, methoxy or carboxy group at the 3'-position of the phenol ring of tyrosine were prepared in an orthogonally protected form suitable for solid-phase peptide synthesis using Fmoc protocols. The incorporation of these residues into cyclic peptides composed of a five-amino acid sequence motif, Xx(1)-Leu-(3'-substituted-Tyr)-Ac6c-Asn, provided a brand new class of nonphosphorylated Grb2 SH2 domain inhibitors with reduced size, charge and peptidic character. The highest binding affinity was exhibited by the 3'-aminotyrosine (3'-NH2-Tyr)-containing (R)-sulfoxide-cyclized pentapeptide (10b) with an IC50 = 58 nM, the first example with low-nanomolar affinity for a five-amino acid long sequence binding to Grb2-SH2 domain free of any phosphotyrosine or phosphotyrosine mimics. However, the incorporation of 3'-NO2-Tyr, 3'-OH-Tyr or 3'-OCH3-Tyr surrogates in the pentapeptide scaffold is detrimental to Grb2-SH2 binding. These observations were rationalized using molecular modeling. More significantly, the best Grb2-SH2 inhibitor 10b showed excellent activity in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with an IC50 value of 19 nM. This study is the first attempt to identify novel nonphosphorylated high affinity Grb2 SH2 inhibitors by the utilization of 3'-substituted tyrosine derivatives, providing a promising new strategy and template for the development of non-pTyr-containing Grb2-SH2 domain antagonists with potent cellular activity, which potentially may find value in chemical therapeutics for erbB2-related cancers.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
9
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1585-96
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16509576-Amino Acid Motifs, pubmed-meshheading:16509576-Antineoplastic Agents, pubmed-meshheading:16509576-Breast Neoplasms, pubmed-meshheading:16509576-Cell Line, Tumor, pubmed-meshheading:16509576-Drug Screening Assays, Antitumor, pubmed-meshheading:16509576-Female, pubmed-meshheading:16509576-GRB2 Adaptor Protein, pubmed-meshheading:16509576-Humans, pubmed-meshheading:16509576-Models, Molecular, pubmed-meshheading:16509576-Oligopeptides, pubmed-meshheading:16509576-Peptides, Cyclic, pubmed-meshheading:16509576-Phosphorylation, pubmed-meshheading:16509576-Protein Binding, pubmed-meshheading:16509576-Receptor, erbB-2, pubmed-meshheading:16509576-Stereoisomerism, pubmed-meshheading:16509576-Structure-Activity Relationship, pubmed-meshheading:16509576-Tyrosine, pubmed-meshheading:16509576-src Homology Domains
pubmed:year
2006
pubmed:articleTitle
Discovery of a novel nonphosphorylated pentapeptide motif displaying high affinity for Grb2-SH2 domain by the utilization of 3'-substituted tyrosine derivatives.
pubmed:affiliation
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural